ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.222T>A (p.Asn74Lys)

dbSNP: rs1553350075
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000537127 SCV000625364 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-06-12 criteria provided, single submitter clinical testing In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with an MSH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 74 of the MSH2 protein (p.Asn74Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine.
Ambry Genetics RCV003372741 SCV004085689 likely benign Hereditary cancer-predisposing syndrome 2023-08-02 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.
All of Us Research Program, National Institutes of Health RCV004003744 SCV004832618 uncertain significance Lynch syndrome 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces asparagine with lysine at codon 74 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.

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