ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2179G>C (p.Ala727Pro)

dbSNP: rs104895026
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000168145 SCV000218805 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-04-06 criteria provided, single submitter clinical testing This sequence change has not been published in the literature and is not present in population databases. This sequence change replaces alanine with proline at codon 727 of the MSH2 protein (p.Ala727Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "deleterious"; PolyPhen-2: “probably damaging”; Align-GVGD: "Class C0").
Ambry Genetics RCV001014647 SCV001175381 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-09 criteria provided, single submitter clinical testing The p.A727P variant (also known as c.2179G>C), located in coding exon 13 of the MSH2 gene, results from a G to C substitution at nucleotide position 2179. The alanine at codon 727 is replaced by proline, an amino acid with highly similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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