ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1688_1689delinsAG (p.Arg563Gln) (rs587780725)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080776 SCV000166380 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132456 SCV000187550 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-07 criteria provided, single submitter clinical testing The c.1688_1689delGAinsAG variant (also known as p.R563Q), located in coding exon 11 of the PMS2 gene, results from an in-frame deletion of GA and insertion of AG at nucleotide positions 1688 to 1689. The arginine at codon 563 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an Asian individual with a personal history of breast cancer (Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral<span style="color:rgb(255, 0, 0)"> by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001263509 SCV000697307 likely benign not specified 2020-10-15 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1688_1689delinsAG (p.Arg563Gln) results in a conservative amino acid change in 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 0.00023 in 276964 control chromosomes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is benign. c.1688_1689delinsAG has been reported in the literature in one individual affected with Breast Cancer (Chan_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000587523 SCV000806184 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132456 SCV000902632 likely benign Hereditary cancer-predisposing syndrome 2016-07-14 criteria provided, single submitter clinical testing

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