Submissions for variant NM_000535.7(PMS2):c.916G>A (p.Val306Met)

gnomAD frequency: 0.00004  dbSNP: rs587780063

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656943	SCV000149619	uncertain significance	not provided	2024-04-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or breast cancer in the published literature (PMID: 29596542, 30521064, 35449176); This variant is associated with the following publications: (PMID: 30521064, 29596542, 32980694, 35449176, 11574484, 36243179)
Ambry Genetics	RCV000115710	SCV000185566	likely benign	Hereditary cancer-predisposing syndrome	2022-11-23	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469956	SCV000552057	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 306 of the PMS2 protein (p.Val306Met). This variant is present in population databases (rs587780063, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 30521064, 31391288, 32661327, 34326862). ClinVar contains an entry for this variant (Variation ID: 127801). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656943	SCV000601864	uncertain significance	not provided	2024-10-17	criteria provided, single submitter	clinical testing	The PMS2 c.916G>A (p.Val306Met) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 29596542 (2018), 30521064 (2019), 32661327 (2020)), breast cancer (PMIDs: 34326862 (2021), 35449176 (2022)), and an unspecified Lynch syndrome-associated cancer (PMID: 31391288 (2020)). This variant has also been observed in reportedly healthy individuals (PMIDs: 32980694 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared), 36243179 (2022)). The frequency of this variant in the general population, 0.000021 (6/282508 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000115710	SCV000686257	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 306 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 30521064) and an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 6/282508 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.
Baylor Genetics	RCV003460827	SCV004205466	uncertain significance	Lynch syndrome 4	2023-08-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997295	SCV004839884	uncertain significance	Lynch syndrome	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 306 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 30521064) and an individual affected with an unspecified cancer (PMID: 31391288). It was also found in control individuals from large breast and pancreatic cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 6/282508 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.
PreventionGenetics, part of Exact Sciences	RCV004742261	SCV000806227	uncertain significance	PMS2-related disorder	2024-05-15	no assertion criteria provided	clinical testing	The PMS2 c.916G>A variant is predicted to result in the amino acid substitution p.Val306Met. This variant has been reported in an individual with colorectal cancer, non-polyposis (Table e2, Jiang et al. 2019. PubMed ID: 30521064), as well as in a patient with colorectal cancer in which the variant was not expected to have been the cause of disease (S Table 2. Hampel et al. 2018. PubMed ID: 29596542). In a breast cancer risk study, this variant was seen in zero breast cancer cases and in three control cases (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD and is classified as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127801/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093686	SCV001250868	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing