Submissions for variant NM_000535.7(PMS2):c.386C>T (p.Ala129Val)

gnomAD frequency: 0.00001  dbSNP: rs752284380

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000233053	SCV000285132	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-17	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 129 of the PMS2 protein (p.Ala129Val). This variant is present in population databases (rs752284380, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of PMS2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 237915). 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.
Ambry Genetics	RCV000566584	SCV000674257	likely benign	Hereditary cancer-predisposing syndrome	2022-12-20	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.
Counsyl	RCV000662749	SCV000785531	uncertain significance	Lynch syndrome 4	2017-09-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000566584	SCV000906810	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 129 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 been identified in 5/251142 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.
Fulgent Genetics, Fulgent Genetics	RCV002503891	SCV002815354	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2021-10-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662749	SCV004019837	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662749	SCV004207909	uncertain significance	Lynch syndrome 4	2022-02-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998793	SCV004842112	uncertain significance	Lynch syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 129 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 been identified in 5/251142 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.