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 2020-08-25 criteria provided, single submitter clinical testing The p.V501M variant (also known as c.1501G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1501. The valine at codon 501 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Invitae RCV000227751 SCV000285073 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-30 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001530922 SCV000697299 uncertain significance not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1501G>A (p.Val501Met) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 364708 control chromosomes, predominantly at a frequency of 7.8e-05 within the Non-Finnish European subpopulation in the gnomAD database (v2.1 exomes- and v3.1 genomes dataset). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than the estimated maximum allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), suggesting that the variant could be a benign polymorphism. However, the variant is located in a region that is highly homologous to a PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. The variant, c.1501G>A, has been reported in the literature as a germline variant in an individual affected with a tumor that belongs to the Lynch syndrome tumor spectrum (Li_2020), and in another individual affected with breast cancer, but was also found in several healthy controls (Dorling_2021, through LOVD). In addition, the variant was reported as somatic variant in a Lynch syndrome-associated tumor (Vargas-Parra_2017). 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. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588840 SCV000888394 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing
Color Health, Inc 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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