ClinVar Miner

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

gnomAD frequency: 0.00142  dbSNP: rs149202766
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Total submissions: 8
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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 Does not segregate with disease in family study (genes with incomplete penetrance);Subpopulation frequency in support of benign classification
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 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 799 of the PMS2 protein (p.Arg799Trp). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with suspected Lynch syndrome, breast and/or ovarian cancer, or pancreatic cancer (PMID: 24072394, 26483394, 28449805, 28528518). ClinVar contains an entry for this variant (Variation ID: 91340). An algorithm developed specifically for the PMS2 gene suggests that this missense change is likely to be deleterious (PMID: 26333163). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000215298 SCV000697346 likely benign not specified 2020-02-25 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 (v2.1) database, including 1 homozygote. Furthermore, the variant allele was found at a frequency of 0.001393 in 140750 control chromosomes, predominantly at a frequency of 0.01250 within the Latino subpopulation in the gnomAD (v3) database, including 8 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD (v3) database is approximately 114-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 8 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. 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 2021-05-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764720 SCV000895855 uncertain significance Turcot syndrome; Colorectal cancer, hereditary nonpolyposis, type 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

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