ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.58C>T (p.Arg20Trp) (rs573374779)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198784 SCV000254616 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 20 of the PMS2 protein (p.Arg20Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs573374779, ExAC 0.03%). This variant was reported in individuals with suspected Lynch syndrome or hereditary breast and ovarian cancer syndrome (PMID: 25980754, Invitae). However, in one of these individuals a pathogenic allele was also identified in PMS2, which suggests that this c.58C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 216461). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 2018-09-11 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Insufficient or conflicting evidence
Counsyl RCV000410798 SCV000489705 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-11-09 criteria provided, single submitter clinical testing
Color RCV000218260 SCV000911707 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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