ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1688G>A (p.Arg563Gln) (rs63750668)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129896 SCV000184714 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001081618 SCV000253291 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000478617 SCV000565693 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1688G>A at the cDNA level, p.Arg563Gln (R563Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been reported in an individual with breast cancer (Liu 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). PMS2 Arg563Gln 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 Arg563Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000662634 SCV000785319 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-06 criteria provided, single submitter clinical testing
Color RCV000129896 SCV000903394 likely benign Hereditary cancer-predisposing syndrome 2016-05-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662634 SCV001320992 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV001193855 SCV001363003 likely benign not specified 2019-12-03 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1688G>A (p.Arg563Gln) 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 0.00027 in 251182 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Non-Polyposis Colon Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1688G>A has been reported in the literature in individuals affected with breast cancer (Balogh_2006, Liu_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.

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