ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.475G>A (p.Val159Met) (rs142416537)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235195 SCV000149605 uncertain significance not provided 2018-07-17 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.475G>A at the cDNA level, p.Val159Met (V159M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in individuals with a personal and/or family history of colorectal, breast, and/or stomach cancer (Chubb 2015, Lu 2015, Haraldsdottir 2017). PMS2 Val159Met was observed at an allele frequency of 0.014% (16/111,290) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). This variant is located within motif IV of the ATPase domain (Guarn? 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 Val159Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000123087 SCV000166387 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 159 of the PMS2 protein (p.Val159Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs142416537, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with colon, stomach, and breast cancer (PMID: 25559809, 26689913, 28466842). ClinVar contains an entry for this variant (Variation ID: 127791). 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: "Deleterious"; PolyPhen-2: "Possibly 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.
Ambry Genetics RCV000115696 SCV000184308 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000115696 SCV000686207 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-04 criteria provided, single submitter clinical testing
Mendelics RCV000708998 SCV000838195 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765968 SCV000897389 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000987848 SCV001137323 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing

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