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

dbSNP: rs587780725

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080776	SCV000166380	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132456	SCV000187550	likely benign	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001263509	SCV000697307	likely benign	not specified	2023-01-06	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=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000587523	SCV000806184	uncertain significance	not provided	2018-01-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132456	SCV000902632	likely benign	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492543	SCV004239588	uncertain significance	Breast and/or ovarian cancer	2022-12-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587523	SCV004704418	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PMS2: BP1