ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.917T>A (p.Val306Glu) (rs786201878)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232471 SCV000285163 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-01-12 criteria provided, single submitter clinical testing This sequence change replaces valine with glutamic acid at codon 306 of the PMS2 protein (p.Val306Glu). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 237933). 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 disruptive, 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.
Ambry Genetics RCV000565783 SCV000676174 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-22 criteria provided, single submitter clinical testing Insufficient evidence
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853300 SCV000996143 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2018-05-04 criteria provided, single submitter clinical testing This variant has not been previously published in the literature to our knowledge, but has been previously reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/237933/). The Val306Glu variant was not observed in large population cohorts and is absent from the ExAC and gnomAD population databases, thus it is presumed to be rare. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect and this variant is located in the ATPase domain. This variant has been observed in the homozygous state in an individual with a clinical history suggestive of a congenital mismatch repair deficiency (CMMR-D) at an independent commercial genetic testing laboratory. Based on the available evidence, the Val306Glu variant is classified as likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001174830 SCV001338196 uncertain significance not specified 2020-02-27 criteria provided, single submitter clinical testing Variant summary: PMS2 c.917T>A (p.Val306Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251190 control chromosomes (gnomAD). 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.917T>A in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.

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