ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2174C>T (p.Ala725Val) (rs150630090)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164743 SCV000215415 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000206423 SCV000260118 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 725 of the PMS2 protein (p.Ala725Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in individuals affected with breast cancer and Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25186627, 25980754). ClinVar contains an entry for this variant (Variation ID: 185339). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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.
Counsyl RCV000410095 SCV000488728 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000486892 SCV000565827 uncertain significance not provided 2018-04-23 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2174C>T at the cDNA level, p.Ala725Val (A725V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has been reported at least twice, in an individual with breast cancer and another with a Lynch syndrome-associated cancer and/or polyps (Tung 2015, Yurgelun 2015). PMS2 c.2174C>T was not observed in large population cohorts (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 Ala725Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761045 SCV000890960 uncertain significance Germinoma (disease) 2016-07-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781746 SCV000920035 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2174C>T (p.Ala725Val) results in a non-conservative amino acid change located in the MutL C-terminal dimerization domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.2e-05 in 89782 control chromosomes (ExAC). This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (2.2e-05 vs 1.10e-04), allowing no conclusion about variant significance. c.2174C>T has been reported in the literature in individuals affected with Lynch Syndrome (Yurgelun_2015, Tung_2014). 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.8167G>C, p.Asp2723His), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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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