Submissions for variant NM_000535.7(PMS2):c.354C>T (p.Ser118=)

gnomAD frequency: 0.00001  dbSNP: rs760615315

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165593	SCV000216327	likely benign	Hereditary cancer-predisposing syndrome	2014-09-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000165593	SCV000686195	likely benign	Hereditary cancer-predisposing syndrome	2016-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479038	SCV000697364	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.354C>T (p.Ser118Ser) 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. Consensus agreement among computation 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 9.2e-06 in 326304 control chromosomes (gnomAD; Okawa_2023). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.354C>T has been reported in the literature in individuals affected with breast cancer without strong evidence of causality (Hu_2022). This report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variant was reported in one of these individuals (MSH2 c.2633_2634del, p.Glu878fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35449176, 36243179). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely benign (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000587468	SCV000732676	likely benign	not provided	2019-04-25	criteria provided, single submitter	clinical testing
Invitae	RCV000630377	SCV000751333	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150025	SCV003838398	uncertain significance	Breast and/or ovarian cancer	2022-05-26	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587468	SCV001743525	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587468	SCV001972299	likely benign	not provided		no assertion criteria provided	clinical testing