ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1576G>T (p.Asp526Tyr) (rs63750686)

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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 RCV000165677 SCV000216415 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000227646 SCV000285076 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 526 of the PMS2 protein (p.Asp526Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs63750686, ExAC 0.03%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 186139). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000679352 SCV000568930 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1576G>T at the cDNA level, p.Asp526Tyr (D526Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAC>TAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. 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 not located in a known functional domain. Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, splicing models predict the creation of a novel splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether PMS2 Asp526Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165677 SCV000686142 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679352 SCV000806181 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679352 SCV001134582 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175050 SCV001338587 uncertain significance not specified 2020-04-17 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1576G>T (p.Asp526Tyr) results in a non-conservative amino acid change in 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 2.8e-05 in 251074 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1576G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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