Submissions for variant NM_000535.7(PMS2):c.857A>G (p.Asp286Gly)

gnomAD frequency: 0.00011  dbSNP: rs116788608

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588331	SCV000149615	uncertain significance	not provided	2024-08-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 26517685, 24728327, 26689913, 28503720, 11574484, 28726808, 31992580, 34680242, 30760869, 34326862, 31391288, 35430768, 37536918, 33471991)
Ambry Genetics	RCV000115706	SCV000216880	likely benign	Hereditary cancer-predisposing syndrome	2021-03-22	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	RCV000197094	SCV000254618	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000409948	SCV000488997	uncertain significance	Lynch syndrome 4	2016-08-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115706	SCV000686246	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 286 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). 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 individuals affected with breast, pancreatic, ovarian and colorectal cancer and/or polyps (PMID: 28503720, 26689913, 26517685, 25980754, 28726808, 31391288, 34680242, 33471991) and in healthy individuals (PMID: 24728327, 33471991). Two of these individuals, one affected with ovarian cancer and the other suspected of Lynch syndrome, also had a pathogenic MSH6 co-variant (PMID: 26689913, 26517685). This variant has been identified in 36/282838 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	RCV000121861	SCV000697393	likely benign	not specified	2023-11-09	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.857A>G (p.Asp286Gly) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) within the S5 domain 2-like fold (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 1614058 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.857A>G has been reported in the literature in several individuals affected with Lynch Syndrome-related cancers (e.g., Yurgelun_2015, Li_2020, Wang_2020, Jori_2016, Rummel_2017, Svensson_2022, Frostberg_2021, Chaffee_2018), however without strong evidence for causality (e.g., lack of co-segregation data) in all cases. In one of these cases a co-occurrence with a pathogenic variant was reported (MSH6 c.2569_2572del, p.Asp857Phefs10*; Jori_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 28726808, 26517685, 31391288, 26689913, 30760869, 28503720, 35430768, 25980754, 31992580, 34680242, 34326862, 37536918). Ten submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n = 7; likely benign, n = 3). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000708992	SCV000838189	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588331	SCV000888418	uncertain significance	not provided	2024-03-15	criteria provided, single submitter	clinical testing	The PMS2 c.857A>G (p.Asp286Gly) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 35430768 (2022), 34680242 (2021), 31992580 (2020)), Lynch syndrome-associated cancer or polyps (PMID: 25980754 (2015)), breast cancer (PMIDs: 34326862 (2021), 28503720 (2017)), ovarian cancer (PMID: 26689913 (2015)), pancreatic cancer (PMID: 28726808 (2018)), leukemia (PMID: 30760869 (2019)), and liposarcoma (PMID: 37536918 (2023)). It has also been observed in reported healthy individuals (PMIDs: 24728327 (2014), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). In an individual with endometrial cancer, this variant co-occurred with a pathogenic variant in the MSH6 gene, suggesting it was not the primary cause of disease (PMID: 26517685 (2015)). The frequency of this variant in the general population, 0.0002 (26/129148 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000765960	SCV000897381	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798338	SCV002042817	uncertain significance	Breast and/or ovarian cancer	2021-01-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409948	SCV004019791	likely benign	Lynch syndrome 4	2023-04-04	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.
Baylor Genetics	RCV000409948	SCV004205340	uncertain significance	Lynch syndrome 4	2024-01-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708992	SCV004839898	uncertain significance	Lynch syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 286 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). 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 individuals affected with breast, pancreatic, ovarian and colorectal cancer and/or polyps (PMID: 28503720, 26689913, 26517685, 25980754, 28726808, 31391288, 34680242, 33471991) and in healthy individuals (PMID: 24728327, 33471991). Two of these individuals, one affected with ovarian cancer and the other suspected of Lynch syndrome, also had a pathogenic MSH6 co-variant (PMID: 26689913, 26517685). This variant has been identified in 36/282838 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000708992	SCV005913374	likely benign	Lynch syndrome	2023-03-21	criteria provided, single submitter	clinical testing
ITMI	RCV000121861	SCV000086063	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144656	SCV000189983	uncertain significance	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003326121	SCV001749542	not provided	Lynch syndrome; Mismatch repair cancer syndrome 4		no assertion provided	phenotyping only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000588331	SCV001808752	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588331	SCV001954994	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742260	SCV005361576	uncertain significance	PMS2-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The PMS2 c.857A>G variant is predicted to result in the amino acid substitution p.Asp286Gly. This variant has been reported in two individuals with suspected Lynch syndrome, however, one these individuals also carried a pathogenic MSH6 variant (Yurgelun et al. 2015. PubMed ID: 25980754; Jori et al. 2015. PubMed ID: 26517685). Additionally, this variant was also present in an individual with ovarian cancer (Lu et al. 2015. PubMed ID: 26689913), an unrelated patient with breast cancer (Rummel. 2017. PubMed ID: 28503720), and an unrelated patient with pancreatic cancer (Supp. Table 2, Chaffee et al. 2018. PubMed ID: 28726808). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127798/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.