ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.994G>A (p.Val332Ile) (rs1236095389)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545777 SCV000625717 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 332 of the PMS2 protein (p.Val332Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 455754). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Integrated Genetics/Laboratory Corporation of America RCV000590366 SCV000697406 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.994G>A (p.Val332Ile) variant located in the Ribosomal protein S5 domain 2-type fold (via Interpro) causes a missense change involving the alteration of a conserved nucleotide and 4/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant is absent in 113932 control chromosomes (ExAC, 1000 Gs, or ESP). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
University of Washington Department of Laboratory Medicine, University of Washington RCV000758684 SCV000887456 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing PMS2 NM_000535.5:c.994G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 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.
Color RCV000775689 SCV000910100 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775689 SCV001181360 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing Insufficient evidence

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