Submissions for variant NM_000535.7(PMS2):c.1364C>T (p.Ser455Phe)

gnomAD frequency: 0.00001  dbSNP: rs748698776

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167069	SCV000217897	likely benign	Hereditary cancer-predisposing syndrome	2018-06-08	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.
Invitae	RCV000226423	SCV000285067	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 455 of the PMS2 protein (p.Ser455Phe). This variant is present in population databases (rs748698776, gnomAD 0.004%). This missense change has been observed in individual(s) with endometrial and colorectal cancer (PMID: 23017166, 27443514). ClinVar contains an entry for this variant (Variation ID: 187347). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454673	SCV000540068	uncertain significance	not specified	2016-10-13	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Missense variant in PMS2 (Ser to Phe). Max MAF is 0.003% (high for PMS2 related CRC). Classified in ClinVar as VUS by Invitae and Ambry (2 stars). Variant is not reported in the literature. 24 species have Phe at this site.
Color Diagnostics, LLC DBA Color Health	RCV000167069	SCV000911128	likely benign	Hereditary cancer-predisposing syndrome	2017-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001753568	SCV002006700	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with endometrial and colon cancer (Clendenning et al., 2013; Ring et al., 2016); This variant is associated with the following publications: (PMID: 23017166, 27443514)
Sema4, Sema4	RCV000167069	SCV002529787	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-25	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753568	SCV002774703	uncertain significance	not provided	2022-04-28	criteria provided, single submitter	clinical testing