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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Cancer 1/2017

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Zeitschrift:
BMC Cancer > Ausgabe 1/2017
Autoren:
Benedito Mauro Rossi, Edenir Inêz Palmero, Francisco López-Kostner, Carlos Sarroca, Carlos Alberto Vaccaro, Florencia Spirandelli, Patricia Ashton-Prolla, Yenni Rodriguez, Henrique de Campos Reis Galvão, Rui Manuel Reis, André Escremim de Paula, Luis Gustavo Capochin Romagnolo, Karin Alvarez, Adriana Della Valle, Florencia Neffa, Pablo German Kalfayan, Enrique Spirandelli, Sergio Chialina, Melva Gutiérrez Angulo, Maria del Carmen Castro-Mujica, Julio Sanchez de Monte, Richard Quispe, Sabrina Daniela da Silva, Norma Teresa Rossi, Claudia Barletta-Carrillo, Susana Revollo, Ximena Taborga, L. Lena Morillas, Hélène Tubeuf, Erika Maria Monteiro-Santos, Tamara Alejandra Piñero, Constantino Dominguez-Barrera, Patrik Wernhoff, Alexandra Martins, Eivind Hovig, Pål Møller, Mev Dominguez-Valentin
Abbreviations
AMS
Amsterdam
AMSII
Amsterdam II criteria
CRC
colorectal cancer
HGMD
Human Gene Mutation Database
HGVS
Human Genome Variation Society
IHC
immunohistochemical
InSIGHT
International Society of Gastrointestinal Hereditary Tumors
LOVD
Leiden Open Variation Database
LS
Lynch syndrome
MMR
mismatch-repair gene
MSI
microsatellite instability
MSI-H
MSI high
MSI-L
MSI low
MSS
microsatellite stable
path_MLH1
Pathogenic (disease-causing) variant of the MLH1 gene
Path_MMR
Pathogenic (disease-causing) variant of an MMR gene.
path_MSH2
Pathogenic (disease-causing) variant of the MSH2 gene
path_MSH6
Pathogenic (disease-causing) variant of the MSH6 gene
path_PMS2
Pathogenic (disease-causing) variant of the PMS2 gene
UMD
Universal Mutation Database

Background

LS is caused by a defective mismatch repair (MMR) system, due to the presence of germline defects in at least one of the MMR genes, MLH1, MSH2, MSH6, PMS2, or to deletions of the 3′ portion of the EPCAM gene [ 1]. Such variants are here referred to as path_MMR and, when specifying one of the genes, as path_MLH1, path_MSH2, path_MSH6, path_PMS2 or path_EPCAM [ 2, 3]. LS is clinically classified according to the Amsterdam (AMS) criteria and/or the Bethesda guidelines, both relying in clinical information and family history. The Bethesda guidelines also takes into account the microsatellite instability (MSI) tumor marker, which is a signature characteristic of MMR-deficient tumors [ 47]. MSI or immuno-histochemical (IHC) testing of tumors are strategies to select patients for subsequent germline diagnostic testing in blood [ 8].
LS patients have an increased lifetime risk of colorectal cancer (CRC) (70–80%), endometrial cancer (50–60%), stomach cancer (13–19%), ovarian cancer (9–14%), cancer of the small intestine, the biliary tract, brain as well as carcinoma of the ureters and renal pelvis [ 9]. The cumulative incidence of any cancer at 70 years of age is 72% for path_MLH1 and path_MSH2 carriers but lower in path_MSH6 (52%) and path_PMS2 (18%) carriers. Path_MSH6 and path_PMS2 carriers do not have an increased risk for cancer before 40 years of age [ 2, 3]. The identification of LS patients is a goal because an early diagnosis and intensive screening may predict the disease and/or improve the disease prognosis [ 2].
The path_MMR variant spectrum of LS has been widely studied in CRC patients from North America, Europe, Australia and Asia. In the past decade, significant advances have been made in molecular testing and genetic counseling for LS in several Latin America countries [ 1051].
A broad definition of Latin America is that all countries of the Americas south of the United States are included, with Mexico, Cuba, Puerto Rico and all the countries located in South America as well as the Caribbean Islands. Latin America presents with genetically somewhat different populations, where European and African immigrants have a concentration of the Caucasian population in the southern regions of the continent, whereas in the northern region, the population is predominantly Mestizo (a mixture of European and Amerindian) [ 52].
Among LS patients, the prevalence of path_ MLH1 is 42%, path_ MSH2 is 33%, path_ MSH6 is 18% and path_ PMS2 is 8% [ 53]. However, recent studies in Latin America LS families described the predominance of path_ MSH2 (46%- 66%), followed by path_ MLH1 (25%–43%), path_ MSH6 (7%–8%), path_ PMS2 (2%) and path_ EPCAM (2%) [ 32, 36, 47]. Some Latin America LS variant spectrum included variants that have not previously been reported and potential founder effects which are useful for future development of genetic testing in these populations. It enables the comparison of LS characteristics and MMR variants across genetic ancestry background differences among these populations [ 12, 20, 23, 26, 32, 36, 40].
The clinical, molecular and MMR variant spectrum of LS has not been fully studied in all Latin America countries. Our study aims to combine both unpublished register data and published data in order to better describe the LS molecular profile and to update the previously described South American path_MMR variant spectrum study [ 32].

Methods

Unpublished data from hereditary cancer registries and published data from patients with suspected LS from Latin America have been included in this work. Through research collaborations, data from the Latin America hereditary cancer registers are available following direct contact with the register. The data include results from germline DNA testing, tumor testing (based on MSI analysis and/or IHC) and family history (Fig.  1).

Hereditary cancer registries

Families that fulfilled the AMSII criteria [ 4, 5], the Bethesda guidelines [ 6] and/or other criteria i.e. families suggestive of a dominant CRC inheritance syndrome were selected from 11 hereditary cancer registries from 8 countries: Hospital Italiano (Buenos Aires, Argentina), Hospital Español de Rosario (Rosario, Argentina), Hospital Privado Universitario de Cordoba (Cordoba, Argentina), Centro de Enfermedades Neoplasicas Oncovida (La Paz, Bolivia), Barretos Cancer Hospital (Barretos, Brazil), Hospital de Clinicas de Porto Alegre (Rio Grande do Sul, Brazil), Clinica Las Condes (Santiago, Chile), Clinica del Country (Bogota, Colombia), Instituto Nacional de Cancerologia (Mexico City, Mexico), Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) and Hospital de las Fuerzas Armadas (Montevideo, Uruguay).
Patients were informed about their inclusion into the registries, which generally contained data on family history, clinical information, age at onset and results of DNA testing or tumor screening in the diagnosis of LS. Written informed consent was obtained from all participants during genetic counseling sessions.

LS databases

A systematic review was performed in order to identify published reports on MMR variants in LS or hereditary CRC by querying the PubMed, SciELO and Google databases using specific key words (focusing on clinical, tumor or genetic testing information associated with the MMR genes) and taking into account publications in three languages, namely Spanish, English and Portuguese, up to July 2016. The search terms were “Lynch syndrome”, “hereditary colorectal cancer”, “hereditary colorectal cancer and Latin America” and “Lynch syndrome and Latin America”. We also used keywords in association with the names of Latin America countries (e.g., “Lynch syndrome and Colombia”). The results of the search were subsequently screened for the presence of path_MMR variants or tumor screening, clinical diagnosis and family history.
We found 34 LS reports from 12 countries including Argentina [ 10, 14, 17, 18], Brazil [ 11, 15, 19, 22, 25, 28, 29, 37, 38, 43], Chile [ 20, 31], Colombia [ 12, 16, 23, 48], Mexico [ 27, 44, 49, 51], El Salvador and Guatemala [ 51], Paraguay [ 50], Peru [ 24, 33, 35, 45], Puerto Rico and Dominican Republic [ 21, 36], South America [ 26, 32, 47] and Uruguay [ 13].

Germline DNA testing

Genetic testing was generally based on Sanger sequencing of MLH1, MSH2, MSH6 and/or PMS2 and/or EPCAM in 7 participating centers from Argentina (Hospital Italiano de Buenos Aires and Hospital Español de Rosario), Brazil (Barretos Cancer Hospital and Hospital de Clinicas de Porto Alegre), Chile (Clinica Las Condes), Colombia (Clinica del Country) and Uruguay (Hospital de Las Fuerzas Armadas). Multiplex Ligation-dependent Probe Amplification (MLPA) was used to analyze genomic rearrangements in MMR and EPCAM genes (SALSA kit P003, MRC-Holland, Amsterdam, Netherland). For PMS2 analysis, especially for exons 12 to 15, to ensure the correct analysis of PMS2 and to avoid pseudogene co-amplification, a long-range PCR followed by a nested PCRs strategy was adopted. After amplification, sequencing was performed according to the manufacturer’s instructions.
In addition, we took into consideration the results of germline DNA testing described in 15 previously published LS reports [ 10, 13, 17, 18, 20, 23, 26, 31, 32, 36, 37, 44, 47, 48, 51].

Tumor testing

Methods to assess tumor MMR status, e.g. MSI analysis and/or MMR protein staining are being currently used in Cordoba (Argentina), Lima (Peru), La Paz (Bolivia) and Mexico City (Mexico) as an approach to identify potential carriers of germline path_MMR variants. Germline MMR testing is then mandatory to confirm LS cases.
Families from Peru (Instituto Nacional de Enfermedades Neoplasicas) were evaluated for MSI using a 5-mononucleotide marker panel (BAT-25, BAT-26, D2S123, D17S250 and D5S346). Tumors were classified into three categories and defined as MSI high (MSI-H) when ≥2 markers were unstable, MSI low (MSI-L) when one marker was unstable and microsatellite stable (MSS) when none of the markers were unstable. In Bolivia (Centro de Enfermedades Neoplasicas Oncovida), MSI analysis was evaluated by 1-mononucleotide marker panel (BAT-26).
IHC analysis for MMR protein expression was performed on paraffin-embedded tumor tissue sections, as previously described [ 32]. In Argentina (Hospital Privado Universitario de Cordoba), Mexico (Instituto Nacional de Cancerologia) and Peru, IHC was evaluated using 4-MMR proteins (MLH1, PMS2, MSH2 and MSH6).
Besides the information directly retrieved from these participating centers, we also collected MSI and/or IHC data from 15 LS published reports [ 1416, 18, 21, 22, 24, 25, 27, 28, 31, 35, 38, 43, 45].

Family history

Available data of family history of patients with CRC included 4 published reports from Brazil [ 19], Mexico [ 49], Paraguay [ 50] and Peru [ 33].

MMR variants nomenclature and classification

The nomenclature guidelines of the Human Genome Variation Society (HGVS) were used to describe the detected MMR variants [ 54]. Variants were described by taking into account the following reference sequences: NM_000249.2 ( MLH1), NM_000251.2 ( MSH2), NM_000179.2 ( MSH6), and NM_001322014.1 ( PMS2). The recurrence or novelty of the identified variants was established by interrogating four databases (in their latest releases as of August 2016): the International Society of Gastrointestinal Hereditary Tumors (InSIGHT) database (accessed via the Leiden Open Variation Database/LOVD), the Universal Mutation Database (UMD), ClinVar, and the Human Gene Mutation Database (HGMD).
The MMR variants were classified according to the 5-tier classification system into the following categories: class 5 (pathogenic), class 4 (likely pathogenic), class 3 (uncertain variants), class 2 (likely not pathogenic) and class 1 (not pathogenic) [ 55]. Novel MMR variants were considered class 5 if they: a) introduced a premature stop codon in the protein sequence (nonsense or frameshift); b) occurred at the most conserved positions of donor or acceptor splice sites (i.e. IVS ± 1, IVS ± 2); or c) represented whole-exon deletions or duplications.
Well established polymorphisms, Class 1 variants and Class 2 variants were considered normal variants and not included in this study, except for the MSH6 c.733A > T, which has conflicting interpretations of pathogenicity. We focused on Class 3, Class 4 and Class 5 variants in this study.
In addition, we updated our previous South American LS study [ 32] according to the 5-tier classification system, with InSiGHT updates [ 55].

Splicing-dedicated bioinformatics analysis

The potential impact on RNA splicing induced by the MMR variants was evaluated by focusing on alterations of donor and acceptor splice sites. We took into consideration both the potential impairment of reference splice sites and the possibility of creation of de novo splice sites. The analysis was performed by using the MaxEntScan algorithm [ 56] interrogated by using the Alamut software (Interactive Biosoftware, France) [ 57, 58]. For stratification purposes, negative alterations of reference splice sites were deemed important when MaxEntScan scores showed ≥15% decrease relative to corresponding wild-type splice sites [ 57]. The possibility of variant-induced de novo splice sites was assessed by annotating all increments in local MaxEntScan scores and comparing their values with those of reference splice sites as well as of nearby cryptic splice sites. In this case and for exonic variants, only scores equal or higher to those of the corresponding reference splice site within the same exon (as well as of local cryptic sites) were considered worth noting. In the case of intronic variants, only scores equal or higher to those of the weakest corresponding reference splice site within the same gene (as well as of local cryptic splice sites) were considered as potentially creating de novo splice sites.

Statistical analysis

Clinical characteristics were described using frequency distributions for categorical variables and summary measures for quantitative variables. To assess comparability of study groups, chi-square test or Fisher’s exact test was used for categorical variables and Student’s t test or Mann-Whitney to compare quantitative variables.
The statistical analyses were performed using the statistical software package IBM SPSS Statistics 20 (SPSS©, Chicago, IL, USA) and STATA 12© (StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP).

Results

Path_MMR variants

By combining data provided by 7 participating centers, we identified suspected LS in a total of 881 Latin America individuals belonging to 344 unrelated families (Table  1, Fig.  1). Path_MMR genes were identified in 47% (range 39–64% depending on the participating countries/registries) of the families that fulfilled the AMSII criteria and/or the Bethesda guidelines and/or other criteria (Table 1). When the AMSII criteria were considered, the path_MMR genes detection raised to 64% (91/142), whereas 32% (54/170) and 23% (11/47) fulfilled the Bethesda guidelines and other criteria, respectively. The range of the mean age at diagnosis was 32–45 years for CRC and 43–51 years for endometrial cancer depending on the countries/registries (Table 1). Of the 410 path _MMR carriers, MLH1 was affected in 53.9% (221/410) of the cases , MSH2 in 32.4% (133/410), MSH6 in 9.5% (39/410), PMS2 in 3.4% (14/410) and EPCAM in 0.8% (3/410) (Table 1).
Table 1
Summary of hereditary cancer registries from Latin America LS families
Latin American Institutions
Number of families
Number of individuals
Families fulfilling a
Path_MMR carriers (%)
Path_MMR families fulfilling
Age at CRC diagnosis (mean ± SD)
Age at endometrial cancer diagnosis (mean ± SD)
AMSII
Revised Bethesda
Other criteria
Path_MMR carriers
Path_MMR non-carriers
Path_MLH1 carriers
Path_MSH2 carriers
Path_MSH6 carriers
Path_PMS2 carriers
Path_EPCAM carriers
AMSII
Revised Bethesda
Other criteria
Barretos Cancer Hospital (São Paulo, Brazil)
125
369
15
95
30
172 (46.6)
197 (53.4)
79 (45.9)
51 (29.7)
32 (18.6)
10 (5.8)
0
12
48
10
na
na
Clinica Las Condes (Santiago, Chile)
100
212
44
47
9
82 (38.7)
130 (61.3)
63 (76.8)
14 (17.1)
0
2 (2.4)
3 (3.7)
24
4
0
40 (10.5)
48.8 (11.5)
Hospital de las Fuerzas Armadas (Montevideo, Uruguay)
29
177
26
1
2
101 (57.1)
76 (42.9)
55 (54.5)
39 (38.6)
7 (6.9)
0
0
19
0
0
39.9 (9.6)
44.4 (11.9)
Hospital Italiano (Buenos Aires, Argentina)
54
75
35
14
5
26 (34.7)
49 (65.3)
11 (42.3)
15 (57.7)
0
0
0
18
0
0
45.8 (7.01)
43.8 (7.08)
Hospital Español de Rosario (Rosario, Argentina)
13
25
6
7
0
16 (64)
9 (36)
5 (31.3)
10 (62.5)
0
1 (6.2)
0
6
2
0
40.4 (10.4)
51 (na)
Hospital das Clinicas (Porto Alegre, Brazil)
18
18
12
6
0
11(61.1)
7 (38.9)
8 (72.7)
3 (27.3)
0
na
0
11
0
0
42.1 (7.8)
na
Clinica del Country (Bogota, Colombia)
5
5
4
0
1
2 (40)
3 (60)
0
1 (50)
0
1 (50)
0
1
0
1
32 (na)
na
Total
344
881
142
170
47
410 (46.5)
471 (53.5)
221 (53.9)
133 (32.4)
39 (9.5)
14 (3.4)
3 (0.8)
91
54
11
   
asome families meet more than one clinical criteria; LS: Lynch syndrome; CRC: colorectal cancer; MMR: mismatch repair; SD: standard deviation; na: not applied; Path_MMR: Pathogenic (disease-causing) variant of an MMR gene; path_MLH1: pathogenic variant of the MLH1 gene; path_MSH2: pathogenic variant of the MSH2 gene; path_MSH6: pathogenic variant of the MSH6 gene; path_PMS2: pathogenic variant of the PMS2 gene
Fifteen published data from Argentina, Brazil, Chile, Colombia, Dominican Republic, El Salvador, Guatemala, Mexico, Puerto Rico, South America and Uruguay contained information about 962 tested individuals belonging to 1514 suspected LS families (Table  2, Fig.  1). Path_MMR variants were identified in 40% (389/962) (range 25–100% in the different databases/countries) of the families that fulfilled the AMSII criteria and/or the Bethesda guidelines and/or other criteria. The range of the mean age at diagnosis was 35–45 years for CRC and 41–49 years for endometrial cancer in the different databases (Table 2). Of the 389 path _MMR carriers, MLH1 was affected in 52.4% (204/389) , MSH2 in 42.7% (166/389), MSH6 in 3.6% (14/389), PMS2 in 0.8% (3/389) and EPCAM in 0.5% (2/389) (Table 2).
Table 2
Summary of published data from Latin America LS families
Latin America LS published databases
Number of families
Number of individuals
Age at CRC diagnosis (mean ± SD)
Age at endometrial cancer diagnosis (mean ± SD)
AMSII
Revised Bethesda
Other criteria
Path_MMR carriers (%)
Path_MMR non- carriers (%)
Path_MLH1 carriers (%)
Path_MSH2 carriers (%)
Path_MSH6 carriers (%)
Path_PMS2 carriers (%)
Path_EPCAM carriers (%)
Mendoza, Argentina [ 10]
1
17
na
na
1
0
0
9(52.9)
8(47.1)
0
9100)
na
na
na
Sao, Paulo, Brazil [ 11]
25
25
45.7(na)
na
6
18
1
10(40)
15(60)
8(80)
2(20)
na
na
na
Montevideo, Uruguay [ 13]
12
12
45
na
12
na
na
3(25)
9(75)
2(67)
1(33)
0
na
na
Bogota, Colombia [ 12, 48]
23
23
na
na
11
12
na
11(47.8)
12(52.2)
10(91)
1(9)
na
na
na
Buenos Aires, Argentina [ 17]
43
11
na
na
43
0
na
5(45.5)
6 (54.5)
2(40)
3(60)
na
na
na
Mexico, El Salvador and Guatemala [ 51]
13
14
38.7(na)
na
5
9
na
11(78.6)
3(21.4)
7(64)
4 (36)
na
na
na
Santiago, Chile [ 20]
21
20
na
na
14
7
na
9(45)
11(55)
6(30)
3(15)
na
na
na
Antioquia, Colombia [ 23]
1
20
na
na
1
na
na
7(35)
13(65)
7(100)
0
na
na
na
Southeastern Brazil, Buenos Aires and Montevideo [ 26]
123
123
na
na
57
66
na
34(27.6)
89(72.4)
20(59)
14(41)
na
na
na
Santiago, Chile [ 31]
35
35
na
na
19
16
na
21(60)
14(40)
14(67)
5(24)
2(9)
na
na
South America [ 32]
267
267
   
147
120
na
99(37.1)
168(62.9)
59(60)
40(40)
na
na
na
Buenos Aires, Argentina
28
na
44.3(6.2)
46.3(5.5)
                   
Montevideo, Uruguay
25
na
35.1(7.6)
41.5(8.3)
                   
Santiago, Chile
50
na
35.7(10.7)
41.1(8.8)
                   
Barretos, Brazil)
23
na
39.4(13.8)
49.8(5.3)
                   
Colombia
13
na
na
na
                   
Southeastern Brazil
128
na
42.3(11.4)
48.8(2.4)
                   
Puerto Rico and Dominican Republic [ 36]
78
31
44.4(na)
44 (na)
na
na
na
22(71)
9 (29)
8(36)
13(59)
1(5)
na
na
Southeastern Brazil [ 37]
116
116
42.4(na)
46 (na)
49
67
na
45(38.8)
71(61)
15(33)
25(56)
4(9)
1(2)
na
Jalisco, Mexico [ 44]
3
5
37.7(na)
na
3
0
na
5(100)
0
4(80)
1(20)
na
na
na
South America [ 47]
243
243
   
na
na
na
98(40.3)
145 (56.7)
42(43)
45(46)
7(7)
2(2)
2(2)
Buenos Aires, Argentina
48
na
44(na)
45(na)
                   
Montevideo, Uruguay
16
na
42.3(na)
48.8(na)
                   
Santiago, Chile
27
na
41.3(na)
43.6(na)
                   
Barretos, Brazil)
23
na
39.4(na)
49.8(na)
                   
Colombia
13
na
na
na
                   
Southeastern Brazil
116
na
42.4(na)
46(na)
                   
Total
1514
962
   
368
315
1
389 (40.4)
573 (59.6)
204 (52.4)
166 (42.7)
14 (3.6)
3 (0.8)
2 (0.5)
LS: Lynch syndrome; CRC: colorectal cancer; MMR: mismatch repair; SD: standard deviation; na: not applied; Path_MMR: Pathogenic (disease-causing) variant of an MMR gene; path_MLH1: pathogenic variant of the MLH1 gene; path_MSH2: pathogenic variant of the MSH2 gene; path_MSH6: pathogenic variant of the MSH6 gene; path_PMS2: pathogenic variant of the PMS2 gene

Latin America MMR variants

In total, 220 unique alterations were identified, including 71 frameshift variants, 50 missense variants, 40 nonsense variants, 36 intronic variants and 23 large deletions/duplications. Frameshift and missense variants were the most common alterations (32% and 23%, respectively), followed by nonsense variants (18%), intronic variants (16%) and large deletions/duplications (11%) (Fig.  2, Table  3).
Table 3
Spectrum of MMR variants in Latin America LS families
Gene
cNomenclature
pNomenclature
Exon
Reported/Current Study classification
References
Country
Number of families
RNA splicing-dedicated in silico analysis
WT MaxEntScan score
Variant MaxEntScan score
Difference in MaxEntScan score between variant and WT (%)
MLH1
c.(?_-198)_116 +?del
 
1
Class 5
InSIGHT
Chile
2
nd
nd
nd
 
c.83C > T
p.Pro28Leu
1
Class 5
InSIGHT
Brazil
2
8.60
8.60
0
 
c.91_92delinsTG
p.Ala31Cys
1
Class 3
InSIGHT
Uruguay
1
8.60
8.60
0
 
c.116G > A
p.Cys39Tyr
1
Class 4
InSIGHT
Argentina
1
8.60
2.61
−70
 
c.117-1G > T
 
1i
Class 5
HGMD
Brazil
1
7.22
0.00
−100
 
c.117-?_207 +?del
p.Cys39 *
2
Class 5
InSIGHT
Brazil
1
nd
nd
nd
 
c.117-691_306 + 1011del
p.Cys39Trpfs *6
2–3
Class 5
InSIGHT
Mexico
1
7.22
7.22
0
 
c.119delT
p.Leu40 *
2
Class 5
InSIGHT
Uruguay
1
7.22
7.25
0
 
c.122A > G
p.Asp41Gly
2
Class 3
InSIGHT
Brazil
1
7.22
7.22
0
 
c.199G > A
p.Gly67Arg
2
Class 5
InSIGHT
Argentina
1
10.45
10.45
0
 
c.211G > T
p.Glu71 *
3
Class 5
InSIGHT
Brazil
1
8.11
8.11
0
 
c.225delT
p.Ile75Metfs
3
Not reported/Class 5
Current study
Brazil
1
8.11
8.11
0
 
c.289 T > G
p.Tyr97Asp
3
Class 3
32
Uruguay
2
9.85
9.85
0
 
c.306 + 5G > A
 
3i
Class 5
UMD, HGMD
Brazil
1
9.85
7.20
−27
 
c.307-2A > G
 
1i
Class 5
UMD (modified from 51)
Guatemala
1
10.90
0.00
−100
 
c.332C > T
p.Ala111Val
4
Class 4
InSIGHT
Brazil
1
10.90
10.90
0
 
C.336 T > A
p.His112Gln
4
Class 3
32
Argentina
1
10.90
10.90
0
 
c.350C > T
p.Thr117Met
4
Class 5
InSIGHT
Uruguay, Argentina
5
8.73
8.73
0
 
c.421C > G
p.Pro141Ala
5
Class 3
12
Colombia
1
10.65
10.65
0
 
c.454-501_546-1098del
p.Glu153Phefs *8
5i
Class 5
InSIGHT
Uruguay
1
6.39
6.39
0
 
c.503dupA
p.Asn168Lysfs *4
6
Class 5
InSIGHT
Chile
1
8.68
8.68
0
 
c.503delA
p.Glu172Asnfs *30
6
Class 5
32
Brazil
1
8.68
8.68
0
 
c.545 + 3A > G
p.Glu153Valfs *9
6i
Class 5
InSIGHT
Brazil
2
8.68
4.95
−43
 
c.588 + 2 T > A b
 
7i
Class 4
26
Brazil
1
9.72
0.00
−100
 
c.588 + 5G > C
 
7i
Class 3
InSIGHT
Brazil
1
9.72
4.33
−55
 
c.588 + 5G > T
 
7i
Not reported
Current study
Argentina
1
9.72
3.64
−63
 
c.665delA
p.Asn222Metfs *7
8
Class 5
InSIGHT
Uruguay
4
9.22
9.22
0
 
c.676C > T
p.Arg226 *
8
Class 5
InSIGHT
Argentina, Mexico
2
9.22
7.12
−23
 
c.677G > A c
p.Gln197Argfs *8
8
Class 5
InSIGHT
Argentina, Brazil
2
9.22
5.00
−46
 
c.677 + 1G > A
 
8i
Class 4
InSIGHT
Brazil
2
9.22
0.00
−100
 
c.677 + 5G > A
 
8i
Class 4
UMD
Chile, Argentina
2
9.22
4.42
−52
 
c.779 T > G
p.Leu260Arg
9
Class 5
InSIGHT
Brazil
1
10.43
10.43
0
 
c.790 + 1G > A
p.Glu227_Ser295del
9i
Class 5
InSIGHT
Chile, Colombia
3
10.43
0.00
−100
 
c.791–4_795delTTAGATCGT
 
10
Class 5
26
Brazil
2
9.42
0.00
−100
 
c.794G > C d
p.Arg265Pro
10
Not reported
80
Chile
1
9.42
9.42
0
 
c.884 + 5 T > C
 
10i
Not reported
Current study
Argentina
1
9.43
10.52
12
 
c.888_890delAGAinsC
p.Leu296Phefs
11
Not reported/Class 5
Current study
Brazil
1
10.46
10.46
0
 
c.901C > T
p.Gln301 *
11
Class 5
InSIGHT
Chile
1
10.46
10.46
0
 
c.911delA
p.Asp304Valfs *63
11
Not reported/Class 5
Current study
Uruguay
1
10.46
10.46
0
 
c.997_1000delAAGC
p.Lys333Serfs *33
11
Class 5
78
Chile
1
7.20
7.20
0
 
c.1013A > G
p.Asn338Ser
11
Class 3
InSIGHT
Brazil
1
7.20
7.20
0
 
c.1023delG
p.Met342Cysfs *25
11
Class 5
InSIGHT
Puerto Rico
2
7.20
7.20
0
 
c.1038 + 1G > T
p.Thr347PhefsX14
11i
Class 5
31
Chile
1
7.20
0.00
−100
 
c.1039-6delT
 
11i
Not reported
Current study
Argentina
2
7.50
9.13
22
 
c.1039-8T_1558?896Tdup
p.520Vfs564X
12–13
Class 5
23
Colombia
2
nd
nd
nd
 
c.1105dupT
 
12
Class 5
Modified from 51
Mexico
1
7.50
7.50
0
 
c.1225_1259del
p.Gln409 *
12
Class 5
UMD
Mexico
1
9.99
9.99
0
 
c.1276C > T
p.Gln426 *
12
Class 5
InSIGHT
Brazil
7
9.99
9.99
0
 
c.1333C > T
p.Gln445 *
12
Class 5
68
Brazil
1
9.99
9.99
0
 
c.1360G > C
p.Gly454Arg
12
Class 3
InSIGHT
Uruguay
1
9.99
9.99
0
 
c.1459C > T
p.Arg487 *
13
Class 5
InSIGHT
Brazil
1
11.66
11.66
0
 
c.1500_1502delCAT c,d
p.Ile501del
13
Class 3
11
Brazil
1
9.15
9.15
0
 
c.1558 + 1G > T
p.Val520Glyfs *3
13i
Class 5
InSIGHT
Brazil
1
9.15
0.00
−100
 
c.1559-2A > C b
p.Leu521Lysfs *34
13i
Class 4
InSIGHT
Chile
1
10.44
0.00
−100
 
c.1559-?_1731 +?del
p.Val520Glyfs *7
14–15
Class 5
31
Chile
1
nd
nd
nd
 
c.1639_1643dupTTATA
p.Leu549Tyrfs *44
14
Class 5
InSIGHT
Brazil
1
6.62
6.62
0
 
c.1681dupT
p.Tyr561Leufs
11
Not reported/Class 5
Current study
Brazil
1
8.17
8.17
0
 
c.1690_1693delCTCA
p.Leu564PhefsTer26
15
Class 5
InSIGHT
Brazil
1
8.17
8.17
0
 
c.1724G > A
p.Arg575Lys
15
Class 3
32
Argentina
1
11.78
11.78
0
 
c.1731 + 3A > T b
p.(Ser556Argfs *14)
15i
Class 4
20
Chile
1
11.78
5.63
−52
 
c.1732-?_1896 +?del
p.Pro579_Glu633del
16–17
Class 5
InSIGHT
Brazil
1
nd
nd
nd
 
c.1763 T > C
p.Leu588Pro
16
Class 3
InSIGHT
Chile
1
9.34
9.34
0
 
c.1852_1854 delAAG d
p.Lys618del
16
Class 5
InSIGHT
Argentina, El Salvador, Mexico
6
3.51
3.51
0
 
c.1853delAinsTTCTT
p.Lys618Ilefs *4
16
Class 5
26
Brazil
2
3.51
3.51
0
 
c.1855delG d
p.Ala619Leufs *18
16
Class 5
12, 36
Colombia, Puerto Rico
3
3.51
3.51
0
 
c.1863delG
p.Met621Ilefs
16
Not reported/Class 5
Current study
Brazil
1
3.51
3.51
0
 
c.1890dup c
p.Asp631 *
16
Class 3
26
Argentina
1
3.51
3.51
0
 
c.1897-?_1989 +?del
p.Glu633_Glu663del
17
Class 5
InSIGHT
Brazil
1
nd
nd
nd
 
c.1897-?_2271 +?del
 
17–19
Class 5
InSIGHT
Brazil
4
nd
nd
nd
 
c.1918C > T
p.Pro640Ser
17
Class 3
InSIGHT
Colombia
1
6.53
6.53
0
 
c.1975C > T
p.Arg659 *
17
Class 5
InSIGHT
Brazil
2
7.70
7.70
0
 
c.1990–93 C > T
 
17i
Not reported
Current study
Argentina
1
5.34
5.34
0
 
c.1998G > A
p.Trp666 *
18
Class 5
11
Brazil
1
5.34
5.34
0
 
c.2027 T > C c
p.Leu676Pro
18
Class 3
26
Brazil
1
5.34
5.34
0
 
c.2041G > A *
p.Ala681Thr
18
Class 5
UMD
Chile, Brazil, Colombia
7
5.34
5.34
0
 
c.2044_2045del
p.Met682Valfs *11
18
Class 5
34, 36
Puerto Rico
2
5.34
5.34
0
 
c.2059C > T
p.Arg687Trp
18
Class 5
InSIGHT
Brazil
1
8.68
8.68
0
 
c.2093C > G
p.Ser698 *
18
Class 5
InSIGHT
El Salvador
1
8.68
8.68
0
 
c.2092_2093delTC
p.Ser698Argfs *5
18
Class 5
20
Chile
1
8.68
8.68
0
 
c.2103 + 1G > C
 
18i
Class 4
InSIGHT
Mexico
1
8.68
0.00
−100
 
c.2104-?_(*193_?)del
p.S702_X757del
19
Class 5
31
Chile
2
nd
nd
nd
 
c.2224C > T
p.Gln742 *
19
Class 5
26
Brazil
1
7.82
7.82
0
 
c.2252_2253dupAA
p.Val752Lysfs *32
19
Class 3
InSIGHT
Brazil
1
7.82
7.82
0
 
c.2252_2253delAA
p.Lys751Serfs *3
19
Class 5
InSIGHT
Argentina
1
7.82
7.82
0
MSH2
c. * 32 G > C
 
3’UTR
Not reported
Current study
Argentina
1
6.11
6.11
0
 
c.71delA
p.Gln24Argfs*40
1
Class 5
32
Brazil
1
10.07
10.07
0
 
c.96dupC
p.Thr33Hisfs*49
1
Not reported/Class 5
Current study
Brazil
1
10.07
10.07
0
 
c.112G > T
p.Asp38Tyr
1
Not reported
Current study
Chile
1
10.07
10.07
0
 
c.138C > G
p.His46Gln
1
Class 3
InSIGHT
Uruguay
1
10.07
10.07
0
 
c.166G > T
p.Glu56*
1
Class 5
InSIGHT
Argentina
1
10.07
10.07
0
 
c.174dupC d
p.Lys59Glnfs*23
1
Class 5
32
Brazil
3
10.07
10.07
0
 
c.181C > T
p.Gln61*
1
Class 5
13
Uruguay
1
10.07
10.07
0
 
c.187delG
p.Val63*
1
Class 5
InSIGHT
Brazil
1
10.07
10.07
0
 
c.(?_-68)_211 +?del
 
1
Class 5
InSIGHT
Argentina
1
nd
nd
nd
 
c.(?_-68)_645 +?del
 
1–3
Class 5
InSIGHT
Puerto Rico
2
nd
nd
nd
 
c.(?_-68)_1076 +?del
 
1–6
Class 5
InSIGHT
Argentina
1
nd
nd
nd
 
c.212-?_366 +?del
p.Ala72Phefs*9
2
Class 5
InSIGHT
Chile
1
nd
nd
nd
 
c.226C > T
p.Gln76*
2
Class 5
InSIGHT, UMD
Mexico
1
8.51
8.51
0
 
c.229_230delAG
p.Ser77Cysfs*4
2
Class 5
InSIGHT
Uruguay
1
8.51
8.51
0
 
c.289C > T
p.Gln97*
2
Class 5
InSIGHT
Argentina
1
8.83
8.83
0
 
c.367-168C > T
 
2i
Not reported
Current study
Argentina
2
6.25
6.25
0
 
c.388_389delCA
p.Gln130Valfs*2
3
Class 5
InSIGHT
Brazil, Argentina
3
6.25
6.25
0
 
c.425C > G
p.Ser142*
3
Class 5
InSIGHT
Guatemala
1
6.25
6.25
0
 
c.435 T > G
p.Ile145Met
3
Class 3
InSIGHT
Argentina
1
6.25
6.25
0
 
c.458C > G
p.Ser153Cys
3
Class 3
37
Brazil
1
6.25
6.25
0
 
c.484G > A
p.Gly162Arg
3
Class 5
InSIGHT
Argentina
1
6.25
6.25
0
 
c.518 T > G
p.Leu173Arg
3
Class 3
InSIGHT
Brazil
1
9.88
9.88
0
 
c.528_529delTG
p.Cys176*
3
Class 5
InSIGHT
Brazil
1
9.88
9.88
0
 
c.530_531delAA
p.Glu177Valfs*3
3
Class 5
13
Uruguay
1
9.88
9.88
0
 
c.557A > G
p.Asn186Ser
3
Class 3
UMD
Uruguay
1
9.88
9.88
0
 
c.596delTG
p.Cys199Leufs*15
3
Class 5
12
Colombia
1
9.88
9.88
0
 
c.638dupT
p.Leu213fs
3
Not reported
44
Mexico
1
9.88
9.88
0
 
c.645 + 1_645 + 10delins15
 
3
Not reported/Class 5
Current study
Brazil
1
9.88
0.00
−100
 
c.645 + 791_1076 + 4894del
p.Ile217Glufs*28
4–6
Class 5
InSIGHT
Brazil
1
nd
nd
nd
 
c.711_727del17
p.Ile237Metfs*13
4
Not reported/Class 5
Current study
Brazil
1
7.79
7.79
0
 
c.862C > T
p.Gln288*
5
Class 5
InSIGHT
Brazil
1
10.35
10.35
0
 
c.876_877insC
 
5
Class 5
Modified from 36
Puerto Rico
1
8.59
8.59
0
 
c.897 T > G
p.Tyr299*
5
Class 5
31
Chile
1
8.59
8.59
0
 
Amplification of exon 5
 
5
Class 5
37
Brazil
1
nd
nd
nd
 
c.905 T > A
p.Leu302*
5
Class 5
InSIGHT
Puerto Rico
1
8.59
8.59
0
 
c.914_923delCAGCAGTCAG
p.Ala305Glufs*23
5
Not reported/Class 5
Current study
Argentina
1
8.59
8.59
0
 
c.942 + 3A > T
p.Val265_Gln314del
5i
Class 5
InSIGHT
Brazil
2
8.59
2.54
−70
 
c.943-1G > T
 
5i
Class 5
Modified from 36
Puerto Rico
2
9.59
0
−100
 
c.1046C > G
p.Pro349Arg
6
Class 5
InSIGHT
Argentina
1
9.81
9.81
0
 
c.1076 + 1_1076 + 2delGT
 
6i
Not reported/Class 5
Current study
Brazil
1
9.81
0.00
−100
 
c.1077-?_1276 +?del
p.Leu360Lysfs*16
7
Class 5
InSiGHT
Argentina; Uruguay; Brazil
3
nd
nd
nd
 
c.1077-135_1276 + 119dup
 
7
Class 5
InSiGHT
Brazil
1
8.92
8.92
0
 
c.1143_1144insA
p.Arg382Thrfs*7
7
Class 5
37
Brazil
1
5.25
5.25
0
 
c.1147C > T
p.Arg382*
7
Class 5
InSIGHT
Brazil
1
5.25
5.25
0
 
c.1165C > T
p.Arg389*
7
Class 5
InSIGHT
Colombia
1
5.25
5.25
0
 
c.1215C > A
p.Tyr405*
7
Class 5
InSIGHT
Chile
1
8.92
8.92
0
 
c.1216C > T
p.Arg406*
7
Class 5
InSIGHT
Uruguay
1
8.92
8.92
0
 
c.1224 T > A
p.Tyr408*
7
Not reported/Class 5
InSIGHT
Argentina
1
8.92
8.92
0
 
c.1226_1227delAG
p.Gln409Argfs*7
7
Class 5
InSIGHT
Brazil
1
8.92
8.92
0
 
c.1249delG
p.Val417Leufs*21
7
Class 5
InSIGHT
Brazil
1
8.92
8.92
0
 
c.1255C > T
p.Gln419*
7
Class 5
InSIGHT
Brazil
1
8.92
8.92
0
 
c.1277-?_1386 +?del
p.Lys427Glyfs*4
8
Class 5
InSiGHT
Brazil
1
nd
nd
nd
 
c.1308dupT
 
8
Class 5
Modified from 36
Puerto Rico
1
10.12
10.12
0
 
c.1444A > T
p.Arg482*
9
Class 5
26
Brazil
2
11.59
11.59
0
 
c.1447G > T
p.Glu483*
9
Class 5
InSIGHT
Brazil
1
11.59
11.59
0
 
c.1457_1460del
p.Asn486Thrfsx10
9
Class 5
InSIGHT
Puerto Rico
1
8.85
8.85
0
 
c.1662-2A > G
 
10i
Class 4
UMD, InSIGHT
Argentina
1
8.01
0.00
−100
 
c.1667delT
p. Leu556*
11
Class 5
26
Brazil
1
8.01
8.01
0
 
c.1667_1668insA
p.Thr557Aspfs*5
11
Class 5
11
Brazil
1
8.01
8.01
0
 
c.1705_1706delGA
p.Glu569Ilefs*2
11
Class 5
InSIGHT
Brazil, Puerto Rico
2
8.01
8.01
0
 
c.1738G > T
p.Glu580*
11
Class 5
InSIGHT
Brazil
1
7.82
7.82
0
 
c.1759 + 1G > A
 
11i
Class 4
InSIGHT
Puerto Rico
1
7.82
0.00
−100
 
c.1759 + 57G > T
 
11i
Not reported
Current study
Argentina
1
7.82
7.82
0
 
c.1777C > T
p.Gln593*
12
Class 5
InSIGHT, UMD
Mexico
1
9.05
9.05
0
 
c.1786_1788delAAT
p.Asn596del
12
Class 5
InSIGHT
Brazil
1
9.05
9.05
0
 
c.1861C > T
p.Arg621*
12
Class 5
InSIGHT, UMD
Argentina, Brazil
2
9.05
9.05
0
 
c.1864C > A
p.Pro622Thr
12
Class 3
14
Argentina
1
9.05
9.05
0
 
c.1865C > G
p.Pro622Arg
12
Not reported
InSIGHT
Argentina
1
9.05
9.05
0
 
c.1911delC d
p.Arg638Glyfs*47
12
Class 5
17
Argentina
1
4.78
4.78
0
 
c.1967_1970dupACTT
p.Phe657Leufs*3
12
Class 5
26
Brazil
1
4.78
4.78
0
 
c.2038C > T
p.Arg680*
13
Class 5
InSIGHT
Chile
1
8.23
8.23
0
 
c.2046_2047delTG
p.Val684AspfsX14
13
Class 5
InSIGHT
Argentina
1
8.23
8.23
0
 
c.2078G > A
p.Cys693Tyr
13
Not reported
Current study
Brazil
1
8.23
8.23
0
 
c.2131C > T
p.Arg711*
13
Class 5
InSIGHT
Argentina, Brazil, Chile
4
10.86
10.86
0
 
c.2145del
p.Asp716Thrfs*4
13
Class 5
37
Brazil
1
10.86
10.86
0
 
c.2152C > T
p.Gln718*
13
Class 5
InSIGHT
Brazil
9
10.86
10.86
0
 
c.2178_2179insA
 
13
Class 5
Modified from 51
Mexico
1
10.86
10.86
0
 
c.2185_2192del7insCCCT
p.M729_E731delinsP729_X730
13
Class 5
20
Chile
1
10.86
10.86
0
 
c.2187G > T
p.Met729Ile
13
Class 3
26
Brazil
1
10.86
10.86
0
 
c.2211-?_2458 +?del
p.Ser738Cysfs*3
14
Class 5
InSIGHT
Brazil
1
nd
nd
nd
 
c.2525_2526delAG
p.Glu842Valfs*3
15
Class 5
26
Brazil
2
9.97
9.97
0
 
c.2785C > T
p.Arg929*
16
Class 5
26
Brazil, Uruguay
2
6.11
6.11
0
EPCAM-MSH2
EPCAM-MSH2 (exon1–4) deletion
 
1–4
Class 5
37
Brazil
1
nd
nd
nd
 
c.583C > G
p.Leu195Val
6
Not reported
Current study
Uruguay
1
nd
nd
nd
 
c.555 + 402_*1220del
 
6–9
Not reported/Class 5
LOVD
Chile
1
nd
nd
nd
 
EPCAM:c.(?_1)_(945_?)_MSH2:c.(?_1)_(1076_?)
 
1–6
Class 5
31
Chile
1
nd
nd
nd
MSH6
c.23_26delACAG
p.Tyr8SerfsTer8
1
Not reported/Class 5
Current study
Brazil
1
7.38
7.38
0
 
c.44C > T
p.Pro15Leu
1
Class 3
ClinVar
Uruguay
1
7.38
7.38
0
 
c.124C > T
p.Pro42Leu
1
Class 3
37
Brazil
1
7.38
7.38
0
 
c.457 + 32del
 
2i
Not reported
Current study
Argentina
1
10.77
10.77
0
 
c.458-?_3172del
p.Gly153_Leu1057del
3–4
Class 5
32
Uruguay
1
nd
nd
nd
 
c.663A > C
p.Glu221Asp
4
Class 3
InSIGHT
Uruguay; Argentina
2
10.87
10.87
0
 
c.733A > T *
p.Ile245Leu
4
Conflicting interpretations of pathogenicity
UMD, Insight
Uruguay
1
10.87
10.87
0
 
c.1133_1134delGA
p.Arg378Lysfs*3
4
Not reported/Class 5
Current study
Brazil
1
10.87
10.87
0
 
c.1338A > T
p.Glu446Asp
4
Class 3
37
Brazil
1
10.87
10.87
0
 
c.1483C > T
p.Arg495*
4
Class 5
InSIGHT
Brazil
1
10.87
10.87
0
 
c.1519dupA
p.Arg507Lysfs*9
4
Class 5
UMD
Brazil
2
10.87
10.87
0
 
c.1591C > A
p.Pro531Thr
4
Class 3
UMD, ClinVAr
Uruguay
1
10.87
10.87
0
 
c.1913delInsAGA
p.Leu638GlnfsX11
4
Not reported/Class 5
Current study
Brazil
1
8.91
8.91
0
 
c.1932G > C
p.Arg644Ser
4
Class 3
37
Brazil
1
8.91
8.91
0
 
c.2194C > T
p.Arg732*
4
Class 5
InSIGHT
Brazil
1
8.91
8.91
0
 
c.2308_2312delinsT
p.Gly770Cysfs*4
4
Class 5
UMD
Uruguay
1
8.91
8.91
0
 
c.2332_2335dupCTTT
p.Cys779Serfs
4
Not reported/Class 5
Current study
Brazil
1
8.91
8.91
0
 
c.2379_2380delTG
p.Ala794Hisfs*9
4
Class 5
37
Brazil
1
nd
nd
nd
 
c.2659delC
p.Lys888Serfs*18
4
Not reported/Class 5
Current study
Brazil
1
8.91
8.91
0
 
c.2983G > T
p.Glu995*
4
Class 5
InSIGHT
Brazil
1
8.91
8.91
0
 
c.3023C > T
p.Thr1008Ile
4
Not reported
Current study
Argentina
1
8.91
8.91
0
 
c.3119_3120delTT
p.Phe1040*
4
Class 5
InSIGHT
Puerto Rico
1
8.91
8.91
0
 
c.3487G > T
p.Glu1163*
6
Class 5
37
Brazil
1
10.55
10.55
0
 
c.3557-144G > A
 
6i
Not reported
Current study
Argentina
8
10.29
10.29
0
 
c.3557-185C > T
 
6i
Not reported
Current study
Argentina
1
10.29
10.29
0
 
c.3632 T > C
p.Leu1211Pro
7
Class 5
InSIGHT
Brazil
1
9.14
9.14
0
 
c.3646 + 91 T > C
 
6
Not reported
Current study
Argentina
1
nd
nd
nd
 
c.3772C > G
p.Gln1258Glu
8
Not reported
Current study
Brazil
1
8.35
8.35
0
 
c.3974_3976delAGA
p.K1325del
9
Class 3
37
Brazil
1
6.25
6.25
0
 
c.4071ins4
 
10
Class 3
51
Mexico
1
nd
nd
nd
PMS2
c.23 + 72C > T
 
1i
Class 3
InSIGHT
Argentina
5
8.70
8.70
0
 
c.537 + 187A > G
 
5i
Not reported
Current study
Argentina
4
8.04
8.04
0
 
c.697C > T
p.Gln233*
6
Class 5
InSIGHT
Brazil
1
6.13
6.13
0
 
c.804-1G > T
 
8i
Not reported/Class 5
Current study
Colombia
1
3.54
0.00
−100
 
c.903 + 84 C > T
 
8i
Not reported
Current study
Argentina
1
7.64
7.64
0
 
c.903 + 100 T > G
 
8i
Not reported
Current study
Argentina
1
7.64
7.64
0
 
c.903 + 144G > T
 
8i
Not reported
Current study
Argentina
4
7.64
7.64
0
 
c.1004A > G
p.Asn335Ser
10
Class 3
ClinVar
Uruguay
1
10.00
10.00
0
 
c.1144G > C
p.Gly382Arg
10
Class 3
37
Brazil
1
10.57
7.69
−27
 
c.1211C > G
p.Pro404Arg
11
Class 3
37
Brazil
1
7.77
7.77
0
 
c.1239dup
p.Asp414Argfs*44
11
Class 5
37
Brazil
1
7.77
7.77
0
 
c.1437C > G
p.His479Gln
11
Class 3
InSIGHT
Argentina
1
7.77
7.77
0
 
c.1831dupA
p.Ile611Asnfs*2
11
Class 5
InSIGHT
Argentina
1
9.06
9.06
0
 
c.2016delG
p.Met672Ilefs*16
12
Class 5
31
Chile
1
8.61
8.61
0
 
c.2036 T > C
p.Ile679Thr
12
Class 3
37
Brazil
1
nd
nd
nd
 
c.2182_2184delinsG
p.Thr728Alafs*7
13
Class 5
HGMD
Brazil
2
nd
nd
nd
 
c.2192_2196delTAACT
p.Leu731Cysfs*3
13
Class 5
InSIGHT
Brazil
1
10.75
10.75
0
 
c.2264 T > C
p.Ile755Thr
13
Class 3
37
Brazil
1
nd
nd
nd
 
c.2276-?_2445 +?del
p.Ala759Glyfs*8
14
Class 5
InSIGHT
Chile
1
nd
nd
nd
LS: Lynch syndrome; Novel MMR variants are represented in bold; a: reported as Class 2 by UMD but not assessed by the InSIGHT; b: MMR variant downgraded from Class 5 to Class 4; c: MMR variant downgraded from Class 5 to Class 3; d: MMR variant updated in the nomenclature; nd: not determined
By the MaxEntScan algorithm, we found that 12% of the variants in our cohort are expected to have a negative impact on RNA splicing (Table  3). Indeed, for 27 out of the 220 variants, the MaxEntScan algorithm predicts a significant decrease in splice site strength (>15% decrease in MaxEntScan scores relative to corresponding wild-type splice sites). These include 23 intronic variants (7 within acceptor sites and 16 at donor sites) and 4 exonic variants (located either at the penultimate or at the last position of the exon). Among these variants, 24 are already considered pathogenic (either Class 4 or Class 5, with MaxEntScan scores ranging from −23% to −100% of WT), including 15 variants located at the most conserved positions of the consensus splice sites, i.e. IVS ± 1 or IVS ± 2, and a nonsense mutation located at the penultimate position of MLH1 exon 8. The three-remaining potential splicing mutations are either currently considered as Class 3 ( MLH1 c.588G + 5G > C, and PMS2 c.1144G > C) or have not yet been reported ( MLH1 c.588 + 5G > T). Further studies will be necessary to determine if these three variants cause splicing alterations as predicted by MaxEntScan (decrease in donor splice site strength, MaxEntScan scores ranging from −27% to −55% of WT), and if they are pathogenic or not.
Our in-silico assessment of potential variant-induced de novo splice sites (data not shown) indicates that 3 out of the 220 variants analyzed in this study are likely to create new splice sites. More precisely, MLH1 c.117-1G > T is predicted to destroy the acceptor site of MLH1 exon 2 and to concomitantly create a potential new and stronger acceptor site 5 nucleotides downstream, within the exon; MSH2 c.645 + 1_645 + 10delins15 is expected to destroy the donor site of MSH2 exon 3 and to create a new donor site 14 nucleotides downstream the reference site, within intron 8; and PMS2 c.804-1G > T is predicted to destroy the acceptor site of PMS2 exon 8 and to concurrently create a new and stronger acceptor site, 8 nucleotides downstream, within the exon. These in silico predictions support the classification of MLH1 c.117-1G > T, MSH2 c.645 + 1_645 + 10delins15 and PMS2 c.804-1G > T as pathogenic (Table  3).
Though the single nucleotide variants (SNV) were spread over the genes, most frequently affected regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%), exon 4 of MSH6 (65%) and exons 11 and 13 of PMS2 (31% and 23%).
We found that the Latin America LS variant spectrum was broad with 80% (175/220) alterations being private i.e., observed in a single family, 15% (33/220) observed in 2–3 families and 6% (12/220) variants observed in ≥4 families. Forty-one variants (19%) had not previously been reported in LS, and thus herein represent novel genetic variants in the MMR genes (including 10 in MLH1, 13 in MSH2, 11 in MSH6, 5 in PMS2 and 2 in EPCAM). The classification of the remaining 179 variants is indicated in Table  3, 37 variants being currently considered as Class 3, 10 as Class 4, 131 as Class 5 and 1 has conflicting interpretations of pathogenicity (Table 3, Fig.  3). The variants have been submitted to the InSiGHT locus-specific database ( https://​www.​insight-group.​org).
In total, 45 MMR variants identified in at least two families were classified as recurrent. Among these, the MLH1 c.1276C > T and the MSH2 c.2152C > T were identified in ≥7 families from different Brazilian cities and the MLH1 c.665del was identified in 4 unrelated Uruguayan families. Recurrent pathogenic variants shared by more than one South American country, include: the MLH1 c.350C > T, c.1852_1854del and the c.2041G > A. More precisely, the MLH1 c.350C > T was identified in 5 unrelated families from Uruguay and Argentina, the MLH1 c.1852_1854del was detected in 6 unrelated families from Argentina, Brazil, El Salvador and Mexico, and the MLH1 c.2041G > A was observed in 7 unrelated families from Chile, Colombia and Brazil. These variants may thus represent frequent MLH1 variants in South American population. Moreover, we found a high incidence of intronic and not previously reported MSH6 and PMS2 variants in Argentina (Table  3).

Founder variants

Here, we identified 16 international founder variants: 8 in MLH1,7 in MSH2 and 1 in MSH6 pathogenic variants in 27 LS families [ 23, 34, 36, 5974] (Table  4). International founder pathogenic variants detected in >2 unrelated LS families included e.g. MLH1 c.545 + 3A > G identified as an Italian founder pathogenic variant [ 75], MSH2 c.388_389del as a Portuguese founder variant identified in Argentina [ 69]. The MSH2 c.942 + 3A > T was found in 2 unrelated Brazilian families and widely described as a Newfoundland founder variant. It had been identified in different populations and could be considered as a world-wide MSH2 variant [ 26, 64]. The MLH1 c.1039-8T_1558 + 896Tdup has been suggested to represent a founder MMR variant in Colombia [ 23]. In line with the Portuguese influence in Brazil, the MLH1 c.1897-?_2271 +?del encompassing exons 17 to 19 have been identified in 4 unrelated Brazilian families [ 69, 70]. The MLH1 c.2044_2045del have been recently described as a founder variant in Puerto Rico [ 34, 36] and the MSH2 c.1077-?_1276 +?del as a Spanish founder Alu-mediated rearrangement which have been identified in Argentina, Uruguay and Brazil [ 67].
Table 4
Founder mutations found in Latin America LS families
Gene
Founder mutation
Total number of LS families (references)
Origin (comments)
MLH1
c.306 + 5G > A
1 in Brazil [ 61]
Spain
MLH1
c.545 + 3A > G
2 in Brazil [ 75]
Italy
MLH1
c.1039-8T_1558 + 896Tdup
2 in Colombia [ 23]
(no haplotype studies were performed)
MLH1
c.1558 + 1G > T
1 in Brazil [ 65]
Italy
MLH1
c.1732-?_1896 +?del
1 in Brazil [ 66, 72]
Finland
MLH1
c.1897-?_2271 +?del
4 in Brazil [ 70, 68]
Portugal (mutation with an estimated age of 283 years)
MLH1
c.2044_2045del
2 in Puerto Rico [ 34, 36]
Puerto Rico
MLH1
c.2252_2253delAA
1 in Argentina [ 40]
Italy (Northern region)
MSH2
c.(?_-68)_1076 +?del
1 in Argentina[ 63, 71, 73]
Italy and North America
MSH2
c.388_389del
2 in Argentina and 1 in Brazil [ 69]
Portugal
MSH2
c.942 + 3A > T
2 in Brazil [ 64]
Newfoundland (considered a world-wide MSH2 variant)
MSH2
c.1077-?_1276 +?del
1 in Argentina, 1 in Uruguay and 1 in Brazil [ 67]
Spain (Alu-mediated rearrangements)
MSH2
c.1165C > T
1 in Colombia [ 62]
French Canada
MSH2
c.1277-?_1386 +?del
1 in Brazil [ 60]
Italy (Sardinia)
MSH2
c.2185_2192del7insCCCT
1 in Chile [ 20]
Amerindian
MSH6
c.2983G > T
1 in Brazil [ 74]
Finland
LS Lynch syndrome

Update of the MMR variants from the previous South America LS study

Due to changes in InSIGHT classification of variants, 14 variants were altered for the MLH1 gene and 2 for the MSH2 gene, relative to our previous classification in Dominguez-Valentin et al. [ 32]. For MLH1, 3 previously classified Class 5 variants were downgraded to Class 4, while 4 previously classified Class 5 were moved to Class 3 and 3 previously classified Class 5 were moved to Class 1 ( MLH1: c.1558 + 14G > A, c.1852_1853delinsGC, c.1853A > C). Three MLH1 variants were updated in their nomenclature. For MSH2 gene, two variants were updated in their nomenclature (Table  3).

Differences between LS patients according to the path_MMR gene

The clinicopathological characteristics evaluated were similar between path_ MLH1, path_ MSH2, path_ MSH6, path_ PMS2 and path_ EPCAM carriers, except for the mean age at CRC diagnosis for MLH1 (39.6 years) and MSH2 carriers (41.5 years) ( p ≤ 0.05) (Table  5). For path_ MLH1 carriers, we observed that the probands had more family history of CRC (56.4%) than LS-associated cancers (20.1%) and 97% fulfilled the AMSII criteria. LS individuals with path_MSH2, path_MSH6 and path_PMS2 were mostly females (63.5%, 90% and 77.8% respectively). Path_ MSH2 carriers fulfilled AMSII criteria (100%) while path_MSH6 and path_PMS2 carriers had more family history of CRC (30% and 75%, respectively) than LS-associated cancers (10% and 25%, respectively). Path_ EPCAM carriers had a lower number for each clinical characteristic (Table 5). Deviating distributions of the parameters discussed above for path_MSH6 and especially path_PMS2 carriers may have escaped significance due to limited number of carriers included.
Table 5
Clinicopathologic characterization of LS patients acording to the affected MMR gene
Clinical characteristics
Path_MMR carriers
p value
Path_MLH1
Path_MSH2
Path_MSH6
Path_PMS2
Path_EPCAM
Age at CRC diagnosis (mean)*
37.5–41.7 (39.6)*
38.6–41.7 (41.5)*
31.2–43.9 (37.5)
38–58 (48)
38–65 (51.5)
 
Gender (n(%))
 Female
39 (54.2)
40 (63.5)
9 (90)
7 (77.8)
1 (33.3)
 
 Male
33 (45.8)
23 (36.5)
1 (10)
2 (22.2)
2 (66.7)
0.261
Family history of CRC (n(%))
 Yes
53 (56.4)
35 (48.6)
3 (30)
3 (75)
2 (66.7)
 
 No
41 (43.6)
37 (51.4)
7 (70)
1 (25)
1 (33.3)
0.449
Family history LS associated cancers (n(%))
 Yes
27 (20.1)
18 (25)
1 (10)
1 (25)
2 (66.7)
 
 No
107 (79.9)
54 (75)
9 (90)
3 (75)
1 (33.3)
0.135
AMSII/Bethesda criteria (n(%))
 AMSII criteria
131(97)
72(100)
8 (100)
2 (66.7)
2 (66.7)
 
 Bethesda
4 (3)
0
0
0
1 (33.3)
na
 Other criteria
0
0
0
1 (33.3)
   
* P ≤ 0.05; LS: Lynch syndrome; CRC: colorectal cancer; na: not applied; Path_MMR: Pathogenic (disease-causing) variant of an MMR gene; path_MLH1: pathogenic variant of the MLH1 gene; path_MSH2: pathogenic variant of the MSH2 gene; path_MSH6: pathogenic variant of the MSH6 gene; path_PMS2: pathogenic variant of the PMS2 gene; path_EPCAM: pathogenic variant of the EPCAM gene
The analysis was performed based on available information from Hospital de las Fuerzas Armadas, Uruguay (except for the gender); Clinicas Las Condes, Chile; Hospital Italiano, Argentina; Hospital Espanol de Rosario, Argentina; Hospital de Clinicas, Brazil (except for family history of LS associated cancers) and Clinica del Country, Colombia

Tumor testing results

Tumors specimens from 83 individuals from Peru, 6 from Argentina, 61 from Bolivia, and 60 from Mexico were analyzed either by IHC and MSI-testing, MSI-testing only, or IHC only, respectively, (Table  6). Of these, 69 (32.8%) were found to have MMR-deficient tumors as determined by IHC or MSI analysis (Table 6). The range of the mean age at diagnosis was 27–43 years for CRC and 37–52 years for endometrial cancer in the different registries. The prevalence of deficient MMR protein expression (MLH1, MSH2, MSH6, PMS2) among Peruvian, Argentinean and Mexican patients was 48%, 50% and 38%, respectively, with most cases having absence of MLH1 protein (data available upon request). Regardless of their MMR proficiency status (proficient vs. deficient), patients had similar ages at CRC diagnosis and gender (Table  7). As shown in Table 7, family history of CRC was increased in MMR-deficient individuals compared to MMR proficient ( P ≤ 0.05). Interestingly, AMSII criteria were more frequently fulfilled among MMR deficient (42.4%) than MMR-proficient (10.9%) individuals and this difference was statistically significant ( P ≤ 0.05) (Table 7).
Table 6
Summary of hereditary cancer registries data from tumor MMR analysis from suspected Latin America LS families
Latin American Institutions
Number of families
Number of individuals
Age at CRC diagnosis (mean ± SD)
Age at endometrial cancer diagnosis (mean ± SD)
Clinical criteria
MMR deficient (%)
MMR non-deficient (%)
AMSII
Revised Bethesda
Instituto Nacional de Enfermedades Neoplásicas (Lima, Peru) a
82
83
41(13.1)
52(9.01)
22
60
40(48.2)
43(51.8)
Centro de EnfermedadesNeoplasicas Oncovida (La Paz, Boliva) b
46
61
27.7(12.7)
na
46
0
3(4.9)
58(95.1)
Instituto Nacional de Cancerología de México (Mexico City, Mexico) c
23
60
33(14.6)
37.5(12.02)
11
12
23(38.3)
37(61.7)
Hospital Privado Universitario de Cordoba (Cordoba, Argentina) c
6
6
43.3(8.7)
NA
0
6
3(50.0)
3(50.0)
Total
157
210
   
79
78
69(32.8)
141(67.2)
a: MMR deficiency analyzed based on IHC and/or MSI; b: MMR deficiency based on BAT-25 MSI marker; c: MMR deficiency based on IHC; NA: not applied; MMR: mismatch-repair; CRC: colorectal cancer; SD: standard deviation; IHC: immunohistochemistry; MSI: microsatellite instability; MSI-H: MSI-high; MSS: microsatellite stable
Table 7
Comparison of MMR- deficient versus MMR- proficient individuals from suspected Latin America LS families
Clinical characteristics
MMR status
p value
Deficient
Proficient
Age at CRC diagnosis (mean + − SD)
42.47
36.3
 
Gender (n(%))
 Male
27 (39.1)
36 (34.6)
 
 Female
42 (60.9)
68 (65.4)
0.545637
Family history of CRC (n(%))
 Yes
66 (98.5)
40 (87)
 
 No
1 (1.5)
6 (13)
0.012333
Family history Lynch syndrome associated cancers (n(%))
 Yes
14 (20.9)
6 (13)
 
 No
53 (79.1)
40 (87)
0.282626
AMSII/Bethesda criteria (n(%))
 AMSII
28 (42.4)
5 (10.9)
 
 Bethesda
38 (57.6)
41 (89.1)
0.000314
* P ≤ 0.05; CRC colorectal cancer, MMR mismatch repair
Compilation of IHC and MSI data from reports on Latin America LS cases (published results and/or database entries) revealed that 21% had MMR deficiency based on IHC and/or MSI analysis (2.5%–60%). No information was available for the mean age at CRC and endometrial cancer diagnosis (Table  8). This data highlights the importance of genetic testing for LS in these populations.
Table 8
Summary of published data from tumor MMR analysis from suspected Latin America LS families
Latin America published data
Number of families
Number of individuals
Clinical criteria
MMR deficient (%)
MMR non-deficient (%)
Loss IHC
 
MSI
AMSII
Revised Bethesda
Other criteria
MLH1 (%)
PMS2 (%)
MSH2 (%)
MSH6 (%)
PMS1 or MSH3* (%)
MSI-H (%)
MSS (%)
Medellin, Colombia [ 16]
41
41
4
27
10
14 (34.1)
27 (65.9)
na
na
na
na
na
14 (34.1)
27 (65.9)
Rosario Santa Fe, Argentina [ 14]
1
3
1
na
na
1 (33.3)
2 (66.7)
na
na
na
na
na
1 (33.3)
2 (66.7)
Sao Paulo, Brazil [ 15]
106
106
na
na
na
14 (13.2)
92 (86.8)
na
na
na
na
na
14 (13.2)
91 (85.9)
Buenos Aires, Argentina [ 18]
41
40
16
0
25
18 (45)
22 (55)
12 (30)
na
7 (17.5)
na
na
13 (32.5)
17 (42.5)
Minas Gerais, Brazil [ 22]
66
66
8
15
43
15 (22.7)
51 (77.3)
na
na
na
na
na
15 (22.7)
51 (77.3)
San Juan, Puerto Rico [ 21]
164
164
na
na
na
7 (4.3)
157 (95.7)
1 (0.06)
na
6 (3.7)
na
na
1 (0.6)
na
Lima, Peru [ 24]
90
90
na
na
na
35 (38.9)
55 (61.1)
23 (25.6)
18 (20)
4 (4.4)
2 (2.2)
na
26 (28.9)
64 (71.1)
Rio Grande do Sul, Brazil [ 25]
212
197
22
100
0
42 (21.3)
155 (78.7)
na
na
na
na
na
42 (21.4)
155 (78.7)
Mexico City, Mexico [ 27]
10
6
0
5
1
2 (33.3)
4 (66.7)
2 (33.3)
na
0
na
na
na
na
Minas Gerais, Brazil [ 28]
77
77
10
17
10
16 (20.8)
61 (79.2)
na
na
na
na
na
16 (20.8)
61 (79.2)
Santiago, Chile [ 31]
35
35
19
16
na
21 (60)
14 (40)
21 (60)
0
6 (17.1)
4 (11.4)
na
28 (80)
7 (20)
Lambayeque, Peru [ 35]
5
3
5
0
na
1 (33.3)
2 (66.7)
1 (33.3)
1 (33.3)
0
0
na
1 (33.3)
0
Sao Paulo, Brazil [ 37]
118
118
9
52
57
3 (2.5)
115 (97.5)
3 (2.5)
3 (2.5)
5 (4.2)
5 (4.2)
na
12 (10.2)
na
Santo Andre, SP, Brazil [ 43]
48
48
2
na
17
13 (27.1)
35 (72.9)
2 (4.2)
3 (6.3)
0
2 (4.2)
9 (19)
na
na
Lima, Peru [ 45]
28
28
0
0
28
11 (39.3)
17 (60.7)
na
na
na
na
na
11 (39.3)
17 (60.7)
Total
1042
1022
96
232
191
213 (20.8)
809 (79.2)
65 (46.4)
25 (17.9)
28 (20)
13 (9.3)
9 (6.4)
168 (36.9)
287 (63.1)
MMR mismatch repair, MSI microsatellite instabily, MSI-H MSI-high, MSS microsatellite stable; na not applied, SD standard deviation, IHC immunohistochemistry

Family history

Since there are no premonitory signs of susceptibility to LS, family history has been the primary method for identifying patients at risk in Brazil, Mexico, Peru and Paraguay. Four published reports showed that 11.5% (107/931) were selected as likely LS on the basis of a positive family history (Table  9).
Table 9
Summary of family history analysis from published data from suspected Latin America LS families
Latin American Databases
Number of families
Number of individuals
Clinical criteria
Interpreted as Sporadic cases
Suspected LS (%)
Non-suspected LS (%)
Median age at CRC diagnosis
AMSII
Revised Bethesda
Other criteria
Mexico City, Mexico [ 49]
210
210
2
0
56
154
2 (0.95)
208 (99.05)
na
Asuncion, Paraguay [ 50]
324
324
9
0
na
315
9 (2.8)
315 (97.2)
55
Sao Paulo, Brazil [ 19]
311
311
4
41
213
98
45 (31.5)
266 (85.5)
na
Lima, Peru [ 33]
86
86
20
31
80
6
51 (59.3)
35 (40.7)
na
Total
931
931
35
72
349
573
107 (11.5)
824 (88.6)
 
na not applied, MMR mismatch-repair genes, CRC colorectal cancer, LS Lynch syndrome

Discussion

Progress has been achieved throughout the past years regarding a better molecular and clinical characterization of LS in Latin America, which is important for the surveillance and management of high-risk patients and their families [ 2].
Here, we present the first thorough LS investigation in Latin America by taking into account 15 different countries. We found that germline genetic testing for LS is already available in six of these countries (Argentina, Brazil, Chile, Colombia, Uruguay and Puerto Rico). Moreover, in three countries (Bolivia, Peru and Mexico), where genetic testing is not yet implemented, tumor analyses are already performed for identifying patients most likely to carry a path_MMR variant.
According to our data, the contribution from the different MMR genes is apparently slightly higher for MLH1 and MSH2 and lower for MSH6 and PMS2 when comparing to the InSIGHT database and international reports. It is possible that this pattern reflects the recent inclusion of MSH6, PMS2 and EPCAM in LS genetic testing in Latin America molecular diagnostic laboratories but could also reflect population structure [ 32, 48, 76, 77]. Interestingly, the clinicopathological features of path_MMR carriers described in Latin America families are in accordance with other studies, e.g. the AMSII criteria were fulfilled by 64% of the path_MMR carriers [ 37, 77].
This study revealed that the Latin America spectrum of MMR variants is broad with a total of 220 different variants, of which 80% are currently considered as private, whereas 20% are deemed as recurrent. Our data support evidence on a significant contribution from large deletions/duplications in EPCAM and frameshift variants in MLH1 and MSH2. Of the 220 MMR variants, 178 were already listed in the InSiGHT database or previous studies [ 78, 79], whereas 41 have not been previously reported in LS [ 80]. In addition, we observed that MSH2 variants most frequently caused disease in Argentinean LS families. Further studies are needed to elucidate the ancestral origin of MMR variants in this population, which may increase the knowledge on the inheritance of LS among affected Latin America individuals [ 10, 14, 17, 40].
Differences in the spectrum of path_MMR variants between populations could be due to differences in the sample size, clinical criteria, selection bias, as well as, genetic ancestry of the individual populations. For instance, Caribbean Hispanics have higher percentage of African ancestry compared to Argentineans and Uruguay nationals [ 36]. Puerto Ricans are an admixed population of three ancestral populations, including European, Africans and Taínos [ 36]. The South American population is ethnically mixed from American Indian, European, and other ancestries, but the proportions may vary between countries. For instance, European ancestry predominates in Uruguay and Argentina, whereas Brazil includes a more heterogeneous population, which is the result of interethnic crosses between the European colonizers (mainly Portuguese), African slaves, and the autochthonous Amerindians [ 15]. The Peruvian population is a multi-ethnic population with Amerindian (45%), Mestizo (37%), white Spanish influence (15%), as well as other minority ethnic groups, such as African-American, Japanese, and Chinese (3%) [ 24]. In Chile, Colombia and Bolivia, Spanish colonist and American Indian ancestry influence the populations [ 20, 32].
It is well established that awareness of founder variants in a specific geographic area or population can be very helpful in designing cost-effective molecular diagnostic approaches [ 70, 81, 82]. Founder mutations provide molecular diagnostic centers the benefit of unambiguous results and thereby, do not demand high skilled professional training.
The other aim of the study was to investigate if the previously MMR variants identified in South American LS families [ 32] are in accordance with the 5-tier classification system [ 55]. We were able to refine the classification of 16 MLH1 and MSH2 variants.
When the tumor MMR data from original and published studies were combined, up to 33% of suspected LS individuals had MMR deficiency. The frequency of MMR deficiency was lower than that reported in studies focusing in American, Spanish and Australian LS families (56%–72%) but is in line to the reported prevalence of MSI in sporadic CRC among Hispanic patients [ 34, 8386]. These differences could also be a reflect of the differences in the tumor testing methodologies across the countries, e.g. MSI analysis is not widely available in the majority of routine pathology service laboratories, the number of MSI mononucleotide markers varies between laboratories as well as the limitation in the number of MMR proteins analyzed by IHC. Moreover, even if MMR deficiency is a good predictor of carrying a germline path_MMR variant, MMR deficiency can also result from somatic inactivation, most commonly due to methylation of the MLH1 promoter [ 86]. IHC and MSI testing will, however, combined identify most LS patients with high sensitivity and specificity.
In Latin America, low budgets make the issue of integrating genetics into clinical practice a challenge, a situation in which the use of family history becomes important for patient care, as it is a low-cost strategy and a risk assessment tool [ 19]. In this scenario, published family history data from Paraguay, Peru, Brazil and Mexico suggest its use as a triage tool together with IHC and MSI to identify and stratify genetic risk in these populations [ 19]. However, awareness of hereditary cancer among clinicians involved in diagnosis and treatment of CRC is currently low, and families actually meeting the clinical criteria may not be identified [ 77]. In addition, the average life expectancy in Latin America and the Caribbean is 75 years and inequalities persist among and within the countries ( www.​paho.​org). These countries are mainly represented by a young population where family history could be less informative and insensitive for assessing genetic screening for LS.
Limitation on genetic testing has an impact in the evaluation of the patients at risk of hereditary cancer and their relatives, and ultimately increases the burden of cancer for this minority population [ 35]. As mentioned, in Latin America, genetic testing is not routinely available at the public health system, with exception of few studies conducted in research institutes or private institutions. For instance, until recently the coverage of oncogenetic services in Brazil, was restricted to less than 5% of the population. However, a significant advance took place in 2012, when the coverage of genetic testing by private health care plans became mandatory in Brazil, currently covering around 20–30% of the population [ 19, 87].
This work provides a snapshot view of the current LS-associated diagnostics practice/output in Latin America. The limitations of this study include the selection of patients recruited from selected reference centers and/or from a nation-wide public reference hospital for cancer patients that cannot renders a representative sample. Furthermore, the diagnostic methodologies may vary between the countries regarding the coverage of the coding region of the genes tested and the clinical criteria for referral to genetic counseling and testing, thus causing an even larger knowledge gap. Finally, several countries are not represented; for instance, we could not find any reports from Venezuela, Honduras, Nicaragua or Ecuador. It will be important to pursue additional studies on LS in Latin America countries to both increase the knowledge of MMR variants in different populations and to bring additional awareness of this condition to medical professionals and public health leaders in Latin America.

Conclusions

The Latin America LS MMR variants spectrum included new MMR variants, genetic frequent regions and potential founder effect. The present study provides support to set or improve LS genetic testing in these countries. Improving the accessibility, including tertiary care, is vital in low-income and middle-income countries that face an increasing burden of CRC. An early diagnosis and intensive screening may predict the disease and/or improve the disease prognosis. Low cost approaches to reach these ends are discussed.

Acknowledgements

We thank the families for their participation and contribution to this study.

Funding

This work was supported by the Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010).

Availability of data and materials

Data from the Latin America hereditary cancer registers, this is indeed available for researchers following direct contact with the register (thus not freely available online).

Ethics approval and consent to participate

All patients provided an informed consent for inclusion into the Latin America registers during genetic counseling sessions and is in compliance with the Helsinki Declaration. Written informed consent was obtained from all participants during genetic counseling sessions.

Consent for publication

Not Applicable.

Competing interests

The authors declare that they have no competing interests.

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
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