ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.58C>T (p.Arg20Trp)

gnomAD frequency: 0.00003  dbSNP: rs573374779
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198784 SCV000254616 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-08 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 20 of the PMS2 protein (p.Arg20Trp). This variant is present in population databases (rs573374779, gnomAD 0.03%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer syndrome and/or suspected Lynch syndrome (PMID: 25980754, 30093976). ClinVar contains an entry for this variant (Variation ID: 216461). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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.
Ambry Genetics RCV000218260 SCV000273539 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-31 criteria provided, single submitter clinical testing The p.R20W variant (also known as c.58C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 58. The arginine at codon 20 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This alteration was also identified in an Asian individual diagnosed with 2 or more primary cancers (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000410798 SCV000489705 uncertain significance Lynch syndrome 4 2016-11-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000218260 SCV000911707 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-19 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 20 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or colon polyps (PMID: 25980754), breast cancer (PMID: 30093976), and gastric cancer (PMID: 36627197). This variant has been identified in 13/277000 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 RCV000781747 SCV000920036 uncertain significance not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.58C>T (p.Arg20Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 13/271264 control chromosomes at a frequency of 0.0000479, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant was reported in one patient undergoing genetic testing for Lynch syndrome without strong evidence for or against pathogenicity (Yurgelun_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneDx RCV001562874 SCV001785711 uncertain significance not provided 2023-09-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with Lynch syndrome-associated cancers/polyps or breast cancer (Yurgelun et al., 2015; Chan et al., 2018; Zhang et al., 2023); This variant is associated with the following publications: (PMID: 25980754, 30093976, 11574484, 18768816, 36627197, 21239990)
Myriad Genetics, Inc. RCV000410798 SCV004019823 uncertain significance Lynch syndrome 4 2023-04-04 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.
Preventiongenetics, part of Exact Sciences RCV003401082 SCV004105720 uncertain significance PMS2-related condition 2023-01-26 criteria provided, single submitter clinical testing The PMS2 c.58C>T variant is predicted to result in the amino acid substitution p.Arg20Trp. This variant has been reported in an individual with breast cancer and an individual undergoing Lynch syndrome genetic testing (Table S2, Chan et al. 2018. PubMed ID: 30093976; Table S2, Yurgelan et al. 2015. PubMed ID: 25980754). This variant is reported in 0.030% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6045628-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/216461/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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