ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2293G>A (p.Ala765Thr) (rs63750368)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199509 SCV000254405 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 765 of the MSH2 protein (p.Ala765Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 216353). 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 and their clinical significance is uncertain. 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 RCV000215183 SCV000276106 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-04 criteria provided, single submitter clinical testing The p.A765T variant (also known as c.2293G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2293. The alanine at codon 765 is replaced by threonine, an amino acid with similar properties. This alteration was reported as a somatic alteration in a microsatellite mutatotor phenotype gastric tumor (Yamamoto H et al. Gastroenterology, 1999 Jun;116:1348-57). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. <br />
Counsyl RCV000411596 SCV000489033 uncertain significance Lynch syndrome I 2016-08-05 criteria provided, single submitter clinical testing

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