Submissions for variant NM_000535.7(PMS2):c.1634C>G (p.Ser545Cys)

dbSNP: rs557906137

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562900	SCV000663489	likely benign	Hereditary cancer-predisposing syndrome	2023-12-12	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	RCV000562900	SCV000909651	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 545 of 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 hereditary cancer in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796414	SCV000935926	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-06-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 545 of the PMS2 protein (p.Ser545Cys). This variant is not present in population databases (gnomAD no frequency). 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: 480321). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509443	SCV002819431	uncertain significance	not specified	2022-12-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459301	SCV004207875	uncertain significance	Lynch syndrome 4	2022-12-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000893	SCV004844167	uncertain significance	Lynch syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 545 of 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 not been identified 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.