ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1156G>A (p.Asp386Asn)

gnomAD frequency: 0.00001  dbSNP: rs1419725521
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000761062 SCV000890977 uncertain significance Lynch syndrome 2020-10-01 criteria provided, single submitter clinical testing The MSH2 c.1156G>A (p.Asp386Asn) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Seven of seven in silico algorithms predict a deleterious effect on the gene or gene product (PP3), however these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001219957 SCV001391925 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-02-10 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with MSH2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 620607). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 386 of the MSH2 protein (p.Asp386Asn).
Ambry Genetics RCV002352272 SCV002622733 likely benign Hereditary cancer-predisposing syndrome 2024-03-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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