ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2397T>A (p.Asn799Lys)

dbSNP: rs368988823
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001209085 SCV001380506 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-06-23 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: 939657). 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 asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 799 of the MSH2 protein (p.Asn799Lys).
Ambry Genetics RCV002451450 SCV002737292 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-20 criteria provided, single submitter clinical testing The p.N799K variant (also known as c.2397T>A), located in coding exon 14 of the MSH2 gene, results from a T to A substitution at nucleotide position 2397. The asparagine at codon 799 is replaced by lysine, an amino acid with similar properties. This variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly 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 RCV002451450 SCV004356738 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-31 criteria provided, single submitter clinical testing This missense variant replaces asparagine with lysine at codon 799 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). This 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). In a large breast cancer case-control study, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). 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.

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