Submissions for variant NM_000535.7(PMS2):c.1679G>A (p.Cys560Tyr)

dbSNP: rs757989905

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000555211	SCV000625546	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 560 of the PMS2 protein (p.Cys560Tyr). This variant is present in population databases (rs757989905, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 455666). 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.
Ambry Genetics	RCV000574607	SCV000663511	likely benign	Hereditary cancer-predisposing syndrome	2018-11-05	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.
Color Diagnostics, LLC DBA Color Health	RCV000574607	SCV000686152	uncertain significance	Hereditary cancer-predisposing syndrome	2019-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 560 of the PMS2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV003231641	SCV003929950	uncertain significance	not provided	2023-09-26	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; Identified in an individual with breast cancer from The Cancer Genome Atlas (TCGA) cohort (Huang et al., 2018); This variant is associated with the following publications: (PMID: 29684080, 29625052, 30196423, 36451132)
All of Us Research Program, National Institutes of Health	RCV004003760	SCV004844159	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 560 of the PMS2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.