ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1386G>C (p.Gln462His)

dbSNP: rs587781997
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130410 SCV000185272 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-07 criteria provided, single submitter clinical testing The c.1386G>C variant (also known as p.Q462H), located in coding exon 8 of the MSH2 gene, results from a G to C substitution at nucleotide position 1386. The glutamine at codon 462 is replaced by histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 8 and may have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive and direct evidence is insufficient at this time (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000817428 SCV000957986 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-06-29 criteria provided, single submitter clinical testing An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 462 of the MSH2 protein (p.Gln462His). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141770).
GeneDx RCV004700441 SCV005201392 uncertain significance not provided 2023-08-27 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18822302, 9774676, 21120944)

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