Submissions for variant NM_000535.7(PMS2):c.23+7G>C

gnomAD frequency: 0.00002  dbSNP: rs878854047

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000423172	SCV000521985	likely benign	not specified	2016-12-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088041	SCV000562215	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759200	SCV000888405	likely benign	not provided	2017-09-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775888	SCV000910368	likely benign	Hereditary cancer-predisposing syndrome	2018-08-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423172	SCV000920025	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.23+7G>C 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. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found at a frequency of 1.6e-05 (i.e., 4 heterozygotes) in 250330 control chromosomes, predominantly at a frequency of 9.8e-05 in the South Asian subpopulation (gnomAD v2.1, Exomes dataset). Though this frequency is close to the estimated maximal expected allele frequency of a pathogenic PMS2 variant (1.1e-04), pseudogene interference cannot be ruled out and the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.23+7G>C in individuals affected with Lynch syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences	RCV003897873	SCV004717063	likely benign	PMS2-related disorder	2023-07-14	no assertion criteria provided	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).