ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.422G>C (p.Gly141Ala) (rs376931673)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000630216 SCV000751172 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 141 of the PMS2 protein (p.Gly141Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs376931673, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 525863). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759922 SCV000889629 uncertain significance not provided 2018-06-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV001022094 SCV001183790 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV001022094 SCV001341283 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193249 SCV001361977 uncertain significance not specified 2019-11-08 criteria provided, single submitter clinical testing Variant summary: PMS2 c.422G>C (p.Gly141Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251140 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.422G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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