ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1618A>C (p.Ser540Arg)

dbSNP: rs1268933712
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573899 SCV000662344 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-05 criteria provided, single submitter clinical testing The p.S540R variant (also known as c.1618A>C), located in coding exon 10 of the MSH2 gene, results from an A to C substitution at nucleotide position 1618. The serine at codon 540 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000573899 SCV000913127 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-04 criteria provided, single submitter clinical testing This missense variant replaces serine with arginine at codon 540 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001296698 SCV001485669 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-07-18 criteria provided, single submitter clinical testing 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: 479856). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 540 of the MSH2 protein (p.Ser540Arg).
GeneDx RCV001764640 SCV001991464 uncertain significance not provided 2023-12-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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