ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1981G>A (p.Glu661Lys) (rs778531080)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526168 SCV000625571 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 661 of the PMS2 protein (p.Glu661Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs778531080, ExAC 0.003%). This variant has been reported in individuals affected with colorectal cancer (PMID: 27146957, 28466842). ClinVar contains an entry for this variant (Variation ID: 455676). 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 RCV000570004 SCV000663490 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000570004 SCV000691051 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000612299 SCV000712912 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Glu661Lys variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but has been identified in 2/66538 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs778531080). Computational prediction tools and conservation analysis suggest that the p.Glu661Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Glu661Lys variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV001162167 SCV001324105 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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