ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1243G>A (p.Val415Met) (rs138387687)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131757 SCV000186800 likely benign Hereditary cancer-predisposing syndrome 2019-04-29 criteria provided, single submitter clinical testing Other data supporting benign classification;No disease association in small case-control study;In silico models in agreement (benign)
Invitae RCV000198383 SCV000254596 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 415 of the PMS2 protein (p.Val415Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs138387687, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in cohorts of individuals affected with pancreatic cancer (PMID: 26483394) and breast and/or ovarian cancer (PMID: 28528518). ClinVar contains an entry for this variant (Variation ID: 142561). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000586259 SCV000279138 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1243G>A at the cDNA level, p.Val415Met (V415M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in individuals with pancreatic cancer, pediatric acute megakaryoblastic leukemia, and at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Zhang 2015, Hu 2016, Yadav 2016, Cock-Rada 2017). Additionally, this variant was detected in the normal tissue from a patient with ovarian cancer with no loss of heterozygosity observed in the tumor (Lu 2015). 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 analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Val415Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855605 SCV000697289 uncertain significance not specified 2019-01-02 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1243G>A (p.Val415Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 277090 control chromosomes (gnomAD). The observed variant frequency is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), suggesting that the variant is benign. However, the variant is located in a region that is highly homologous to the PMS2 pseudogenes and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.1243G>A has been reported in the literature in individuals affected with various tumor phenotypes (Hu 2016, Zhang 2015, Yadav 2017, Cock-Rada 2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant once as likely benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000708984 SCV000838180 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586259 SCV000888385 uncertain significance not provided 2017-11-22 criteria provided, single submitter clinical testing
Color RCV000131757 SCV000902659 likely benign Hereditary cancer-predisposing syndrome 2016-03-16 criteria provided, single submitter clinical testing
Mendelics RCV000987834 SCV001137303 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987834 SCV001324212 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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