Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the <i>MSH2</i> gene

Lage, Pedro; Albuquerque, Cristina; Sousa, Rita; Cravo, Marília; Salazar, María Fernanda; Francisco, Inês; Maia, Lara; Claro, Isabel; Suspiro, Alexandra; Rodrigues, Pedro Luiz Coelho; Raposo, Hélder; Fidalgo, Paulo; Nobre‐Leitão, Carlos

doi:10.1002/cncr.20320

Cited by 6 publications

(7 citation statements)

References 31 publications

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“…This mutation was previously described as deleterious in the Europe and the USA population [34][35][36][37]. According to our data, there is no evidence that such mutation is associated to related families, therefore, it was considered a hot spot.…”

Section: Spectrum Of Non-pathogenic Mutationsmentioning

confidence: 65%

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

et al. 2011

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Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron-exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.

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Section: Spectrum Of Non-pathogenic Mutationsmentioning

confidence: 65%

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

et al. 2011

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“…For example, a missense variant, p.Arg385Cys, is annotated as "likely pathogenic" in the ClinVar database and a report shows cosegregation with cancer phenotype [42]. However, the same research group later stated that the variant was a "missense variant of unreported pathogenicity" [43]. This variant was found in five individuals in 2KJPN, and further studies are needed to clarify the pathogenic roles of this variant.…”

Section: Lynch Syndrome Genesmentioning

confidence: 99%

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

et al. 2017

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

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“…In addition, none of the previous publications on Portuguese Lynch families mostly from central/south Portugal reported the MSH2 c.388_389del mutation (12)(13)(14)(15)(16)(17), so the geographical distribution we observe is not likely to be explained by a referral bias to our institution. The seven informative Portuguese families with the MSH2 c.388_389del mutation shared an identical microsatellite haplotype covering a chromosomal region of approximately 10 Mb.…”

Section: Discussionmentioning

confidence: 62%

“…All the 16 known Portuguese families are originated from the north of Portugal and, as far as we could go on genealogical studies, these families are not related. In addition, none of the previous publications on Portuguese Lynch families mostly from central/south Portugal reported the MSH2 c.388_389del mutation (12)(13)(14)(15)(16)(17), so the geographical distribution we observe is not likely to be explained by a referral bias to our institution. The shared haplotype length and the limited geographical dispersion in Portugal indicate that the MSH2 c.388_389del alteration is a founder mutation in Portugal with a relatively recent origin.…”

Section: Discussionmentioning

confidence: 62%

The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families

Pinheiro¹,

Pinto²,

Peixoto³

et al. 2012

Clinical Genetics

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The MSH2 c.388_389del mutation has occasionally been described in Lynch families worldwide. At the Portuguese Oncology Institute in Porto, Portugal, we have identified 16 seemingly unrelated families with this germline mutation. To evaluate if this alteration is a founder or a recurrent mutation we performed haplotype analysis in the 16 Portuguese index cases and 55 relatives, as well as in four index cases and 13 relatives reported from Germany, Scotland, England, and Argentina. In the Portuguese families we observed a shared haplotype of approximately 10 Mb and all were originated from the north of Portugal. These results suggest that this alteration is a founder mutation in Portugal with a relatively recent origin. In the reported families outside Portugal with this mutation different haplotype backgrounds were observed, supporting the hypothesis that it occurred de novo on multiple occasions. We also conclude that the high proportion of families with the MSH2 c.388_389del mutation indicates that screening for this alteration as a first step may be cost-effective in the genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the north of Portugal.

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Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene

Cited by 6 publications

References 31 publications

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families

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