ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.751G>A (p.Val251Met) (rs142434011)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587187 SCV000211574 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.751G>A at the cDNA level, p.Val251Met (V251M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Val251Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Val251Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206870 SCV000261020 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-13 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 251 of the PMS2 protein (p.Val251Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs142434011, ExAC 0.005%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 182801). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000160885 SCV000601859 uncertain significance not specified 2017-07-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567432 SCV000663424 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000567432 SCV000686234 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000160885 SCV000697384 uncertain significance not specified 2020-08-24 criteria provided, single submitter clinical testing Variant summary: PMS2 c.751G>A (p.Val251Met) results in a conservative amino acid change located in the N-terminal (IPR002099) and S5 domain 2-like (IPR013507) domains of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250208 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.751G>A has been reported in the literature in at least one individual affected with early onset colorectal cancer (Zhunussova_2019). This report does 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. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
True Health Diagnostics RCV000567432 SCV000805284 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing

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