Submissions for variant NM_000535.7(PMS2):c.993C>T (p.Cys331=)

gnomAD frequency: 0.00009  dbSNP: rs186577215

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223117	SCV000275667	likely benign	Hereditary cancer-predisposing syndrome	2015-05-08	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.
Invitae	RCV000229543	SCV000285168	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223117	SCV000691131	likely benign	Hereditary cancer-predisposing syndrome	2017-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001722189	SCV000729272	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758631	SCV000887388	benign	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	PMS2 NM_000535.5:c.993C>T has a 0.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000613399	SCV001774509	likely benign	not specified	2021-07-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000223117	SCV002530415	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001722189	SCV004219045	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported as a somatic variant in colorectal or endometrial cancer tumors (PMID: 29887214 (2014)). The frequency of this variant in the general population, 0.00028 (7/24808 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 splicing yielded predictions that this variant does not affect PMS2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491979	SCV004239610	likely benign	Breast and/or ovarian cancer	2022-11-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003897493	SCV004712498	likely benign	PMS2-related disorder	2022-04-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000758631	SCV004839865	likely benign	Lynch syndrome	2023-08-08	criteria provided, single submitter	clinical testing