ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2356C>A (p.Leu786Met) (rs576055272)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131526 SCV000186520 likely benign Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Subpopulation frequency in support of benign classification
Invitae RCV001082079 SCV000255292 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000656951 SCV000279150 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2356C>A at the cDNA level, p.Leu786Met (L786M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). PMS2 Leu786Met was identified in at least one individual among a cohort of 145 patients who underwent PMS2 clinical testing, as well as in an individual with previously negative BRCA1/2 analysis (Vaughn 2010, Yadav 2016). 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 Leu786Met is located in the Endonuclease domain (Fukui 2011). In-silico analysis, including protein predictors and evolutionary conservation, supports that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Leu786Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV000218670 SCV000304731 likely benign not specified criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218670 SCV000601844 benign not specified 2017-07-04 criteria provided, single submitter clinical testing
Counsyl RCV000662644 SCV000785331 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131526 SCV000822132 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656951 SCV000892766 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000131526 SCV001251935 benign Hereditary cancer-predisposing syndrome 2020-05-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662644 SCV001322353 benign Hereditary nonpolyposis colorectal cancer type 4 2018-07-23 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Integrated Genetics/Laboratory Corporation of America RCV000218670 SCV001361924 likely benign not specified 2019-01-23 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2356C>A (p.Leu786Met) results in a conservative amino acid change located in the MutL, C-terminal, dimerization domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 244884 control chromosomes, predominantly at a frequency of 0.0087 within the South Asian subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 77 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. However, this observance needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured, although the observance of a total of 10 homozygotes does support the actual PMS2 gene being captured. c.2356C>A has been reported in the literature in individuals with a personal or family history of cancer including colorectal cancer and breast cancer (Yadav 2017, Tung 2015, Roy 2009). However, 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. Six ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as benign (2x), likely benign (1x) and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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