ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.727G>T (p.Val243Phe) (rs867655834)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479913 SCV000566970 uncertain significance not provided 2016-12-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.727G>T at the cDNA level, p.Val243Phe (V243F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val243Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Val243Phe occurs at a position that is conserved in mammals and is located in the ATPase domain (Guarne 2001). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Val243Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000758685 SCV000887457 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing PMS2 NM_000535.5:c.727G>T has a 16.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Invitae RCV001054961 SCV001219323 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 243 of the PMS2 protein (p.Val243Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 29752822). ClinVar contains an entry for this variant (Variation ID: 419274). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV001187833 SCV001354720 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-09 criteria provided, single submitter clinical testing

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