Submissions for variant NM_000535.7(PMS2):c.1463C>T (p.Ala488Val)

gnomAD frequency: 0.00001  dbSNP: rs587779328

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221900	SCV000273766	likely benign	Hereditary cancer-predisposing syndrome	2019-03-12	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000076811	SCV000296931	uncertain significance	Lynch syndrome	2015-10-12	criteria provided, single submitter	clinical testing
Invitae	RCV000684795	SCV000552061	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 488 of the PMS2 protein (p.Ala488Val). This variant is present in population databases (rs587779328, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary cancer (PMID: 27435373). ClinVar contains an entry for this variant (Variation ID: 91303). 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%. Experimental studies have shown that this missense change does not substantially affect PMS2 function (PMID: 27435373). 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.
GeneDx	RCV000657046	SCV000567509	uncertain significance	not provided	2022-12-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with adenomatous colorectal polyps, but demonstrated proficient mismatch repair (MMR) activity in an in vitro MMR assay (van der Klift et al., 2016); This variant is associated with the following publications: (PMID: 26333163, 27435373)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483082	SCV000601818	likely benign	not specified	2017-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221900	SCV000903597	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 488 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). A functional study reported that this variant did not impair DNA mismatch repair activity in vitro (PMID: 27435373). This variant has been detected in a suspected Lynch syndrome family (PMID: 27435373). This variant has been identified in 2/251460 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.
All of Us Research Program, National Institutes of Health	RCV000076811	SCV004844207	uncertain significance	Lynch syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 488 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). TA functional study reported that this variant did not impair DNA mismatch repair activity in vitro (PMID: 27435373). This variant has been detected in a suspected Lynch syndrome family (PMID: 27435373). This variant has been identified in 2/251460 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.