ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2407A>G (p.Thr803Ala) (rs63751168)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543029 SCV000625378 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-07-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 803 of the MSH2 protein (p.Thr803Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with gastric cancer, however, the germline nature of this variant was not ascertained (PMID: 21528233). 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: "Benign"; Align-GVGD: "Class C0"). In addition, an algorithm developed specifically for the MSH2 gene classifies this missense change as a variant of uncertain significance (PMID: 18383312). However, 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.
Integrated Genetics/Laboratory Corporation of America RCV000588000 SCV000696248 uncertain significance not specified 2020-07-10 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2407A>G (p.Thr803Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2407A>G has been reported in the literature in individuals affected with hepatocellular carcinoma, gastric cancer and colorectal cancer (e.g. Hatta_1997, Sakai_2016, Yano_2007). In all instances, the variant was detected in tumor tissue samples and germline incidence was not ascertained. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV001015432 SCV001176263 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-24 criteria provided, single submitter clinical testing The p.T803A variant (also known as c.2407A>G), located in coding exon 14 of the MSH2 gene, results from an A to G substitution at nucleotide position 2407. The threonine at codon 803 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030715 SCV001193637 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Color RCV001015432 SCV001347187 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing

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