ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1211A>G (p.Asn404Ser)

gnomAD frequency: 0.00001  dbSNP: rs768740986
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460255 SCV000551048 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000520334 SCV000618478 uncertain significance not provided 2023-05-01 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 a MMR-proficient colorectal cancer (Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 17531815, 21120944, 27978560)
Ambry Genetics RCV000567415 SCV000669933 likely benign Hereditary cancer-predisposing syndrome 2022-08-26 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 RCV000567415 SCV000685181 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-22 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 404 of the MSH6 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 been reported in an individual affected with early onset colorectal cancer (PMID: 27978560). This variant has been identified in 4/282702 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.
All of Us Research Program, National Institutes of Health RCV004000828 SCV004835342 uncertain significance Lynch syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 404 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). This variant has been identified in 4/282702 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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