Submissions for variant NM_000535.7(PMS2):c.8G>T (p.Arg3Leu)

dbSNP: rs375507981

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000696078	SCV000824625	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3 of the PMS2 protein (p.Arg3Leu). This variant is present in population databases (rs375507981, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 574206). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001177038	SCV001341151	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 3 in the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 10/250274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Ambry Genetics	RCV001177038	SCV002684067	likely benign	Hereditary cancer-predisposing syndrome	2021-07-19	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.
Baylor Genetics	RCV003460944	SCV004205442	uncertain significance	Lynch syndrome 4	2023-09-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999650	SCV004842187	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 3 in the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 10/250274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.