ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.4G>A (p.Ala2Thr) (rs63750466)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000034558 SCV000884129 uncertain significance not provided 2018-02-06 criteria provided, single submitter clinical testing The MSH2 c.4G>A; p.Ala2Thr variant (rs63750466) is reported in the literature in multiple individuals with Lynch syndrome (Kurzawski 2006, Mangold 2005a, Mangold 2005b, Nagasaka 2010, Pagenstecher 2006, Parc 2003). However, it has been reported to co-occur with a pathogenic MSH2 nonsense variant (Mangold 2005a) and a 3'EPCAM deletion where MSH2 promoter methylation was seen (Nagasaka 2010). This variant is also reported to co-segregate with disease in a large Lynch syndrome family where loss of the MSH2 protein was seen in four individual's tumors; however, RNA analysis showed normal expression, suggesting this variant may be a marker in this family but the functional consequences are uncertain (Pagenstecher 2006). This variant is considered uncertain by an expert review panel in ClinVar (Variation ID: 41650), and is found in the general population with an overall allele frequency of 0.01% (34/241756 alleles) in the Genome Aggregation Database. This variant occurs in a conserved nucleotide of the Kozak consensus sequence, but computational algorithms do not agree as to the effect this variant may have on the protein (SIFT: Tolerated, PolyPhen2: Probably Damaging). Based on available information, the clinical significance of p.Ala2Thr is uncertain at this time. REFERENCES Kurzawski G et al. Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). Clin Genet. 2006 Jan;69(1):40-7. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005a Sep 20;116(5):692-702. Mangold E et al. Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol. 2005b Dec;207(4):385-95. Nagasaka T et al. Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. Cancer Res. 2010 Apr 15;70(8):3098-108. Pagenstecher C et al. Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Hum Genet. 2006 Mar;119(1-2):9-22. Parc Y et al. Cancer risk in 348 French MSH2 or MLH1 gene carriers. J Med Genet. 2003 Mar;40(3):208-13.
Ambry Genetics RCV000115534 SCV000184713 likely benign Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),Insufficient or conflicting evidence,No disease association in appropriately sized case-control study(ies),Other data supporting benign classification
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034558 SCV000043334 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000115534 SCV000902739 likely benign Hereditary cancer-predisposing syndrome 2015-02-19 criteria provided, single submitter clinical testing
Counsyl RCV000076617 SCV000488838 uncertain significance Lynch syndrome I 2016-07-05 criteria provided, single submitter clinical testing
GeneDx RCV000034558 SCV000149443 likely benign not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000202071 SCV000696273 likely benign not specified 2019-05-03 criteria provided, single submitter clinical testing MSH2 c.4G>A (p.Ala2Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. This was confirmed by RT-PCR results (Pagenstecher_2006). The variant allele was found at a frequency of 0.00016 in 217422 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (0.00016 vs 0.00057), allowing no conclusion about variant significance. The variant, c.4G>A, has been reported in the literature in individuals affected with Lynch Syndrome, uveal malignant melanoma or autosomal dominant cancer predisposition syndromes (Mangold_2005, Kurzawski_2006, Schrader_2016, Bonadona_2011, Hajkova_2018, Zhang_2015). One publication reported one family where it showed segregation of this variant with Lynch syndrome (Mangold_2005). However, in many reports, not all MMR genes were tested or MLPA applied. Consequently, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Furthermore, in some of these families co-occurrences with other pathogenic variants have been reported (MSH2 c.1835C>G, p.Ser612X (Mangold_2005); EPCAM deletion associated with MSH2 promoter methylation (Nagasaka_2010); MSH2 c.1delA (UMD); RAD51C c.97C>T, p.Gln33X (Internal database)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign (n=4 to include the expert panel), VUS (n=3)). Based on the evidence outlined above, the variant was classified as likely benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076617 SCV000107653 likely benign Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.05 (0.006)
Invitae RCV000206355 SCV000259383 likely benign Hereditary nonpolyposis colon cancer 2018-01-06 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202071 SCV000257190 uncertain significance not specified no assertion criteria provided research
University of Washington Department of Laboratory Medicine,University of Washington RCV000664313 SCV000788246 likely benign Lynch syndrome 2018-02-01 criteria provided, single submitter clinical testing MSH2 p.A2T has been reported to co-occur with a MSH2 nonsense variant and a 3' EPCAM deletion where MSH2 promoter methylation was identified (Mangold 2005, Nagasaka 2010). Functional RNA studies performed on peripheral blood found normal RNA levels in patients that carry p.A2T (Pagenstecher 2006). MSH2 p.A2T was observed at an allele frequency of 0.0724% (14/19320 alleles) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016), and it was observed in 1/208 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012).

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