Submissions for variant NM_000535.7(PMS2):c.572A>G (p.Tyr191Cys)

gnomAD frequency: 0.00029  dbSNP: rs375289386

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132453	SCV000187547	likely benign	Hereditary cancer-predisposing syndrome	2021-05-14	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.
Invitae	RCV001080249	SCV000259736	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000034631	SCV000279132	uncertain significance	not provided	2023-10-03	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: 27647783, 22949387, 22703879, 25980754, 28503720, 29684080, 25186627, 27600092, 33359728, 33471991, 36446039, 35264596, 11574484)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034631	SCV000601853	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00096 (24/24968 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 25186627 (2015), 28503720 (2017), and 33471991 (2021)), prostate cancer (PMID: 36446039 (2022), colorectal cancer (PMID: 33359728 (2022)), and suspected Lynch syndrome (PMID: 25980754 (2015)) as well as unaffected controls (PMIDs: 22703879 (2012) and 33471991 (2021)). 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	RCV000132453	SCV000686220	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 191 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with suspected Lynch syndrome (PMID: 25980754), colorectal cancer (PMID: 29684080, 33359728), and kidney cell carcinoma (PMID: 29684080). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 28503720; Lovejoy 2019), although the variant co-occurred with a truncating TP53 variant in one breast cancer case (PMID: 28503720), and in a large breast cancer case-control study it was observed in one affected individual and one unaffected control (PMID: 33471991). This variant has also been reported in an individual with no reported cancer history (PMID: 22703879). This variant has been identified in 31/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated frequency in the African population (0.0961%) may indicate this variant is a polymorphism. 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	RCV000221255	SCV000697373	likely benign	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.572A>G (p.Tyr191Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein family N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251492 control chromosomes, predominantly at a frequency of 0.00098 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13.8 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 African or African-American origin. Sequence alignment analysis suggests that the variant does not lie within a region of the gene that has high homology with a PMS2 pseudogene, suggesting occurrences reported in gnomAD are from PMS2 and not the pseudogenes. c.572A>G has been reported in the literature in individuals suspected with Lynch Syndrome (Yurgelun_2015) or affected with breast cancer (Rummel_2017, Tung_2015, Guindalino_2022). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with a pathogenic variant has been reported (TP53 c.637C>T, p.Arg213Ter, Rummel_2017), 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: 22703879, 27647783, 28503720, 25186627, 25980754, 35264596). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000662753	SCV000785541	uncertain significance	Lynch syndrome 4	2017-09-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000662753	SCV001137321	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000662753	SCV001482722	uncertain significance	Lynch syndrome 4	2019-07-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798067	SCV002042809	uncertain significance	Breast and/or ovarian cancer	2020-02-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132453	SCV002530362	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000221255	SCV002550752	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662753	SCV004019876	uncertain significance	Lynch syndrome 4	2023-04-05	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034631	SCV004562460	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	The PMS2 c.572A>G; p.Tyr191Cys variant (rs375289386) is reported in the literature in individuals affected with breast cancer or Lynch syndrome (Guindalini 2022, Yurgelun 2015). This variant was found in a breast cancer patient who also carried a pathogenic variant in the TP53 gene (Rummel 2017). This variant is reported in ClinVar (Variation ID: 41715) and is found in the African/African-American population with an allele frequency of 0.096% (24/24,968 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.89). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Guindalini RSC et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci Rep. 2022 Mar 9;12(1):4190. PMID: 35264596. Rummel SK et al. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. Breast Cancer Res Treat. 2017 Aug;164(3):593-601. PMID: 28503720. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. PMID: 25980754.
All of Us Research Program, National Institutes of Health	RCV003996173	SCV004839958	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 191 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with suspected Lynch syndrome (PMID: 25980754), colorectal cancer (PMID: 29684080, 33359728), and kidney cell carcinoma (PMID: 29684080). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 28503720; Lovejoy 2019), although the variant co-occurred with a truncating TP53 variant in one breast cancer case (PMID: 28503720), and in a large breast cancer case-control study it was observed in one affected individual and one unaffected control (PMID: 33471991). This variant has also been reported in an individual with no reported cancer history (PMID: 22703879). This variant has been identified in 31/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated frequency in the African population (0.0961%) may indicate this variant is a polymorphism. 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034631	SCV000043436	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.