ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2267C>G (p.Thr756Ser) (rs372383829)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464961 SCV000548300 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 756 of the MSH2 protein (p.Thr756Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs372383829, ExAC 0.03%). This variant has been observed in an individual affected with endometrial carcinoma (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 408544). 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 RCV000573097 SCV000662255 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000573097 SCV000911377 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781562 SCV000919706 uncertain significance not specified 2018-06-05 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2267C>G (p.Thr756Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 277176 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2267C>G, has been reported in the literature in an individual affected with endometrial carcinoma and was classified as a VUS (Ring_2016). This report does not provide an unequivocal conclusion about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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