ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2542G>T (p.Ala848Ser)

gnomAD frequency: 0.00001  dbSNP: rs746972142
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204877 SCV000260250 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-11-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491044 SCV000580534 likely benign Hereditary cancer-predisposing syndrome 2022-02-08 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.
Color Diagnostics, LLC DBA Color Health RCV000491044 SCV000685053 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-19 criteria provided, single submitter clinical testing This missense variant replaces alanine with serine at codon 848 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study suggests that the variant protein has in vitro DNA mismatch repair activity similar to the wild-type protein (PMID: 19697156). The variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 18547406, 19697156), ovarian cancer (PMID: 23047549), and kidney cancer (PMID: 29684080). This variant has also been identified in 3/282842 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.
GeneDx RCV001570632 SCV001794960 uncertain significance not provided 2023-03-21 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: intact mismatch repair activity and resistance to 6-TG similar to wild type (Christensen et al., 2009; Jia et al., 2020); Identified in individuals with colorectal, breast, ovarian, or renal cancer (Christensen et al., 2009; Pal et al., 2012; Yehia et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 18547406, 29684080, 22290698, 23047549, 18822302, 21120944, 33471991, 19697156, 33357406)
Sema4, Sema4 RCV000491044 SCV002534486 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-10 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV003997603 SCV004826420 uncertain significance Lynch syndrome 2023-07-10 criteria provided, single submitter clinical testing This missense variant replaces alanine with serine at codon 848 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study suggests that the variant protein has in vitro DNA mismatch repair activity similar to the wild-type protein (PMID: 19697156). The variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 18547406, 19697156), ovarian cancer (PMID: 23047549), and kidney cancer (PMID: 29684080). This variant has also been identified in 3/282842 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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