ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2726A>G (p.Lys909Arg)

gnomAD frequency: 0.00001  dbSNP: rs34319539
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197107 SCV000254415 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491688 SCV000580561 likely benign Hereditary cancer-predisposing syndrome 2023-06-15 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.
GeneDx RCV001550881 SCV001771280 uncertain significance not provided 2022-07-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 28135145)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798670 SCV002042105 uncertain significance Breast and/or ovarian cancer 2020-01-13 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997022 SCV004829920 uncertain significance Lynch syndrome 2023-10-06 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 909 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 2/250502 chromosomes 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.

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