Submissions for variant NM_000535.7(PMS2):c.2007-6C>G

dbSNP: rs376018314

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199056	SCV000253294	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587224	SCV000697324	benign	not specified	2021-12-13	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2007-6C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.7e-05 in 149768 control chromosomes (gnomAD). However, the variant was reported in certain subpopulations with an even higher frequency, e.g. in Japanese control individuals (in the jMorp database) the variant occurs with a frequency of 0.0029, which is about 40-fold of the estimated MPAF (7.1e-05) suggesting that the variant could be a benign polymorphism. To our knowledge, no occurrence of c.2007-6C>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported in several internal samples, providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, and considering the lack of the variant in affected cases after an extensive review of literature spanning 6 years (2015 - 2021), the variant was re-classified as benign.
Counsyl	RCV000662636	SCV000785322	uncertain significance	Lynch syndrome 4	2017-07-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150086	SCV003838570	uncertain significance	Breast and/or ovarian cancer	2021-06-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662636	SCV004019851	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477659	SCV004218973	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000095 (2/21112 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on PMS2 mRNA splicing yielded inconclusive findings . Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV003584561	SCV004359575	likely benign	Hereditary cancer-predisposing syndrome	2022-04-28	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000662636	SCV005881043	benign	Lynch syndrome 4	2025-02-01	criteria provided, single submitter	clinical testing