ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1501G>A (p.Val501Met) (rs540287433)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588840 SCV000149569 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1501G>A at the cDNA level, p.Val501Met (V501M) 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 germline variant; however, it has been reported as a somatic variant in a Lynch syndrome-associated tumor (Vargas-Parra 2017). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. 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 Val501Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115660 SCV000186841 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000227751 SCV000285073 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 501 of the PMS2 protein (p.Val501Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs540287433, ExAC 0.006%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127762). 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 tolerated, 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.
Integrated Genetics/Laboratory Corporation of America RCV000588840 SCV000697299 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1501G>A (p.Val501Met) variant causes a missense change involving a non-conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 4/121220 (1/30303), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMS2 variant of 1/8802 and needs to be cautiously considered due to the PMS2 pseudogene possibly being captured. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, although multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588840 SCV000888394 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing
Color RCV000115660 SCV000910743 likely benign Hereditary cancer-predisposing syndrome 2016-04-29 criteria provided, single submitter clinical testing
Mendelics RCV000987828 SCV001137295 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing

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