Submissions for variant NM_000535.7(PMS2):c.2395C>T (p.Arg799Trp)

gnomAD frequency: 0.00142  dbSNP: rs149202766

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162455	SCV000212809	likely benign	Hereditary cancer-predisposing syndrome	2018-12-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000590372	SCV000279151	likely benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of Lynch syndrome-related cancers, at least one of whom had tumor studies consistent with pathogenic variants in this gene (Zahary 2014, Hu 2016, Sunga 2017, Yurgelun 2017, Cock-Rada 2018, Oliver 2019, Li 2020); This variant is associated with the following publications: (PMID: 24072394, 26483394, 26798439, 28135145, 26333163, 28528518, 30979843, 30122538, 31391288, 31921681, 28449805)
Invitae	RCV000524466	SCV000552023	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000215298	SCV000697346	likely benign	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2395C>T (p.Arg799Trp) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain (IPR014790) 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 0.00051 in 238072 control chromosomes, predominantly at a frequency of 0.0031 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. Furthermore, the variant allele was found at a frequency of 0.001391 in 149538 control chromosomes, predominantly at a frequency of 0.01181 within the Latino subpopulation in the gnomAD (v3) database, including 9 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD (v3) database is approximately 107-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. This observation needs to be cautiously considered due to the possibility of the PMS2 pseudogene being captured, although the observation of at least 9 homozygotes, decreases the likelihood of a pseudogene artefact. c.2395C>T has been reported in the literature in sequencing studies of individuals affected with pancreatic cancer, Lynch Syndrome and hereditary breast and ovarian cancer syndrome (e.g. Cock-Rada_2017, Hu_2016, Li_2020, Oliver_2019, Sunga_2017, Yurgelun_2017, Zahary_2014). Specifically, Zahary_2014 reports the variant in one suspected Lynch syndrome patient who was indicated to have absent PMS2 protein expression, although the IHC findings from MLH1 and MSH2 were not provided. Furthermore, co-occurrence and cosegregation data and MLH1 gene testing results were not reported. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in a HBOC patient (BRCA1 c.1674delA, p.Gly559fsX13; Cock-Rada_2017), providing additional supporting evidence for a non-pathogenic role attributed to this variant. The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 26333163, 24072394, 28135145, 28528518, 28449805, 30122538, 31391288, 31921681, 35449176). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4), likely benign (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590372	SCV000888408	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs:35449176 (2022), 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2, 31921681 (2019), 28528518 (2017)), colorectal cancer (PMIDs: 28135145 (2017), 28449805 (2017), 24072394 (2014)), and pancreatic cancer (PMID: 26483394 (2015)), as well as in unaffected individuals in a large breast cancer association study (PMIDs: 33471991 (2021), https://databases.lovd.nl/shared/variants/PMS2). The frequency of this variant in the general population, 0.0031 (108/34802 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000764720	SCV000895855	uncertain significance	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000215298	SCV002070520	uncertain significance	not specified	2021-12-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2395C>T, in exon 14 that results in an amino acid change, p.Arg799Trp. This sequence change has been described in the gnomAD database with a frequency of 0.31% in the Latino/Admixed American subpopulation including one homozygous individual (dbSNP rs149202766). The p.Arg799Trp change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Arg799Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been identified in individuals evaluated for Lynch syndrome, in an individual with pancreatic adenocarcinoma, and in individuals assessed for hereditary breast and ovarian cancer (PMID: 28449805, 28528518, 24072394, 2648339). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg799Trp change remains unknown at this time.
Mendelics	RCV000215298	SCV002519144	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162455	SCV004358995	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 799 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 Lynch syndrome or Lynch syndrome-associated cancers (PMID: 24072394, 28135145, 28449805), breast/ovarian cancer (PMID: 28528518, 31921681 33471991), or pancreatic cancer (PMID: 26483394) This variant has been identified in 119/233620 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in multiple healthy control individuals (PMID: 33471991). This observed population allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153358	SCV003843752	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing