ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1026A>C (p.Gln342His) (rs561993366)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164831 SCV000215514 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000206306 SCV000261318 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 342 of the PMS2 protein (p.Gln342His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 185416). 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: "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.
GeneDx RCV000482141 SCV000566029 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1026A>C at the cDNA level, p.Gln342His (Q342H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAC). This variant was observed in at least one individual with breast cancer, and was also observed in a cohort of patients with Cowden syndrome and Bannayan- Riley-Ruvalcaba syndrome without identifiable PTEN variants (Tung 2015, Yehia 2018). PMS2 Gln342His 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 a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Gln342His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164831 SCV000904178 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001162268 SCV001324215 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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