ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1465G>A (p.Glu489Lys) (rs876660060)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221906 SCV000277161 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000629950 SCV000750906 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 489 of the PMS2 protein (p.Glu489Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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: 232901). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine 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.
Color RCV000221906 SCV000906481 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781759 SCV000920057 uncertain significance not specified 2018-09-14 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1465G>A (p.Glu489Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277220 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.1465G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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