ClinVar Miner

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

dbSNP: rs786201878
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Total submissions: 5
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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 2023-05-25 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 237933). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 306 of the PMS2 protein (p.Val306Glu). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. 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 2021-12-27 criteria provided, single submitter clinical testing The p.V306E variant (also known as c.917T>A), located in coding exon 9 of the PMS2 gene, results from a T to A substitution at nucleotide position 917. The valine at codon 306 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853300 SCV000996143 likely pathogenic Lynch syndrome 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284035 SCV001469607 uncertain significance not provided 2020-03-10 criteria provided, single submitter clinical testing

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