ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2347G>A (p.Val783Ile) (rs553286217)

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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 RCV000165312 SCV000216034 likely benign Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
GeneDx RCV000767022 SCV000279208 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2347G>A at the cDNA level, p.Val783Ile (V783I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant was reported in an individual undergoing multi-gene cancer panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in the endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Val783Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230774 SCV000285117 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 783 of the PMS2 protein (p.Val783Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. The frequency data for this variant in the population databases (rs553286217, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been reported in an individual who was undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 185820). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000222502 SCV000601843 uncertain significance not specified 2016-09-02 criteria provided, single submitter clinical testing
Counsyl RCV000662655 SCV000785342 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 criteria provided, single submitter clinical testing
Mendelics RCV000662655 SCV001137279 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000222502 SCV001363168 uncertain significance not specified 2019-04-22 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2347G>A (p.Val783Ile) results in a conservative amino acid change located in the MutL, C-terminal, dimerisation of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250156 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (5.6e-05 vs 0.00011), allowing no conclusion about variant significance. c.2347G>A has been reported in the literature in an individual being tested for Lynch Syndrome (Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.7008-2A>G; Yurgelun_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four classified as VUS, one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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