Submissions for variant NM_000535.7(PMS2):c.1279C>T (p.Arg427Cys)

gnomAD frequency: 0.00012  dbSNP: rs376042544

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115655	SCV000149564	uncertain significance	not provided	2024-05-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25808843, 35002543)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228417	SCV000285059	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565134	SCV000663455	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-15	criteria provided, single submitter	clinical testing	The p.R427C variant (also known as c.1279C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1279. The arginine at codon 427 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000565134	SCV000686118	likely benign	Hereditary cancer-predisposing syndrome	2020-10-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115655	SCV001134577	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00048 (12/24942 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been briefly reported in a study of prostate cancer (PMID: 32832836 (2020)) as well as in an MMR proficient endometrial tumor that had other clinically significant variants (PMID: 35002543 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
CeGaT Center for Human Genetics Tuebingen	RCV000115655	SCV001371515	uncertain significance	not provided	2020-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415890	SCV004116636	uncertain significance	PMS2-related disorder	2022-11-04	criteria provided, single submitter	clinical testing	The PMS2 c.1279C>T variant is predicted to result in the amino acid substitution p.Arg427Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6027117-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127758/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003467051	SCV004205434	uncertain significance	Lynch syndrome 4	2024-03-28	criteria provided, single submitter	clinical testing