ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1753C>A (p.Leu585Ile) (rs63750947)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216706 SCV000278562 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing The p.L585I variant (also known as c.1753C>A), located in coding exon 11 of the PMS2 gene, results from a C to A substitution at nucleotide position 1753. The leucine at codon 585 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been identified in cis with a pathogenic PMS2 mutation in an HNPCC/Lynch syndrome family and was shown to be mismatch-repair proficient in vitro (Hendriks YM et al. Gastroenterology 2006 Feb; 130(2):312-22; Drost M et al. Hum. Mutat. 2013 Nov; 34(11):1477-80). This alteration has been classified as a variant of unknown significance by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is poorly 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.
GeneDx RCV001529737 SCV000518107 likely benign not provided 2019-05-21 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24027009, 27435373, 16472587, 22290698, 26333163, 28135145)
Invitae RCV000524448 SCV000552041 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 585 of the PMS2 protein (p.Leu585Ile). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs63750947, ExAC 0.002%). This variant has been reported in individuals with suspected Lynch syndrome (PMID: 16472587, 27435373) and colorectal cancer (PMID: 28135145). However, in some of these individuals, the variant was on the same chromosome (in cis) with a pathogenic variant (p.Arg628*) in the PMS2 gene. ClinVar contains an entry for this variant (Variation ID: 91313). In an experimental study, this variant did not have a significant effect on mismatch repair activity compared to wild-type PMS2 (PMID: 24027009). 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.
Color Health, Inc RCV000216706 SCV000911785 likely benign Hereditary cancer-predisposing syndrome 2020-11-03 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000216706 SCV000788109 likely benign Hereditary cancer-predisposing syndrome 2017-07-31 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001529737 SCV001743705 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001529737 SCV001952652 likely benign not provided no assertion criteria provided clinical testing

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