Submissions for variant NM_000535.7(PMS2):c.1240G>T (p.Asp414Tyr)

gnomAD frequency: 0.00001  dbSNP: rs370752614

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586084	SCV000149563	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Observed in an individual with pancreatic cancer who also harbored a CDKN2A pathogenic variant, in individuals with breast cancer, and in unaffected control(s) (Yang et al., 2016; Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31391288, 27449771, 33471991)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123073	SCV000166368	benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000217417	SCV000273974	likely benign	Hereditary cancer-predisposing syndrome	2024-03-04	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	RCV000217417	SCV000691003	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-26	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 414 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 performed for this variant. This variant has been reported in an individual affected pancreatic cancer (PMID: 27449771). In a large breast cancer case-control study, this variant has been reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250702 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855654	SCV000697286	uncertain significance	not specified	2022-01-09	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1240G>T (p.Asp414Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250702 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1240G>T has been reported in the literature in one individual affected with pancreatic cancer, who also carried a pathogenic variant in CDKN2A (co-occurring variant was not specified) (Yang 2016). The variant was also reported as likely benign in one patient diagnosed with a Lynch syndrome related cancer (Li_2020), and within a breast cancer patient cohort (Dorling_2021). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed this variant since 2014: all submitters have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000217417	SCV002529773	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	curation
Baylor Genetics	RCV003460820	SCV004205372	uncertain significance	Lynch syndrome 4	2023-12-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586084	SCV004218945	uncertain significance	not provided	2024-11-16	criteria provided, single submitter	clinical testing	The BRCA2 c.7463G>A (p.Arg2488Lys) variant has been reported in the published literature in an individual with pancreatic cancer (PMID: 27449771 (2016)) and in an individual with a Lynch Syndrome-related cancer (PMID: 31391288 (2020)). In a large scale breast cancer association study, this variant has been observed in 2 breast cancer cases and 1 reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000087 (3/34558 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997286	SCV004839825	uncertain significance	Lynch syndrome	2024-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 414 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 performed for this variant. This variant has been reported in an individual affected pancreatic cancer (PMID: 27449771). In a large breast cancer case-control study, this variant has been reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/250702 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000855654	SCV005090730	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003460820	SCV005404817	likely benign	Lynch syndrome 4	2024-07-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
True Health Diagnostics	RCV000217417	SCV000805281	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742253	SCV005354865	uncertain significance	PMS2-related disorder	2024-04-04	no assertion criteria provided	clinical testing	The PMS2 c.1240G>T variant is predicted to result in the amino acid substitution p.Asp414Tyr. This variant has been reported in an individual with pancreatic cancer who also had a CDKN2A variant (Table S4, Yang et al. 2016. PubMed ID: 27449771). This variant was also reported in an individual with Lynch syndrome-related cancer (Table S5, Li et al. 2020. PubMed ID: 31391288). This variant was also documented in both affected (n=2) and control (n=1) individuals in a breast cancer study (Breast Cancer Association et al. 2021. PubMed ID: 33471991;  https://bcac.ccge.medschl.cam.ac.uk/bcacdata/bridges-summary-results-breast-cancer-risk-genes-2021/). This variant is present in 3 out of ~251,000 alleles in the gnomAD database (https://gnomad.broadinstitute.org/variant/7-6027156-C-A); however, frequency data in this region is considered unreliable due to presence of a pseudogene. This variant has been interpreted as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/127757/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.