ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.485G>C (p.Gly162Ala) (rs63750773)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529963 SCV000625431 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 162 of the MSH2 protein (p.Gly162Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (rs63750773, ExAC no frequency). This variant has been reported in the literature in an individual with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 17128465). ClinVar contains an entry for this variant (Variation ID: 91106). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Gly162Arg) has been determined to be pathogenic (PMID: 17101317, 18781619, 12537652, 18951462, 22949387, 24362816). This suggests that the glycine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Ambry Genetics RCV000568914 SCV000673897 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing Insufficient evidence

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