Submissions for variant NM_000535.7(PMS2):c.1357A>G (p.Met453Val)

gnomAD frequency: 0.00002  dbSNP: rs587780722

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123075	SCV000166370	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 453 of the PMS2 protein (p.Met453Val). This variant is present in population databases (rs587780722, gnomAD 0.002%). 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: 135934). 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	RCV000572231	SCV000663456	likely benign	Hereditary cancer-predisposing syndrome	2018-03-28	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.
Color Diagnostics, LLC DBA Color Health	RCV000572231	SCV000691009	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 453 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with leukemia (PMID: 26689913). This variant has been identified in 2/251490 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.
Sema4, Sema4	RCV000572231	SCV002529786	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	curation
GeneDx	RCV002466437	SCV002762322	uncertain significance	not provided	2022-11-30	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 an individual with a personal history of cancer (Kiyozumi et al., 2019); This variant is associated with the following publications: (PMID: 31386297)