ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1490G>A (p.Gly497Asp) (rs199739859)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115659 SCV000186706 likely benign Hereditary cancer-predisposing syndrome 2017-05-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign)
Color RCV000115659 SCV000902676 likely benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
Counsyl RCV000663092 SCV000786190 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-03-14 criteria provided, single submitter clinical testing
GeneDx RCV000656948 SCV000149568 uncertain significance not provided 2018-11-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1490G>A at the cDNA level, p.Gly497Asp (G497D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant was observed in at least three individuals with colorectal cancer, one of whom had a tumor demonstrating microsatellite stability, and was also reported in individuals with endometrial and breast cancer, respectively (Chubb 2015, Tung 2015, Ring 2016, Yurgelun 2017). Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Gly497Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000115659 SCV000822122 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000121849 SCV000086049 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000121849 SCV000920047 uncertain significance not specified 2018-05-07 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1490G>A (p.Gly497Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant of interest was observed with an allele frequency of 1.2e-05 in 246190 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (1.2e-05 vs 0.00011), allowing no conclusion about variant significance. The variant, c.1490G>A, has been reported in the literature in individuals affected with Lynch Syndrome (Chubb_2015, Ring_2016, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant predominantly as "uncertian significance" (3x), and 1x as "likely benign." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000123081 SCV000166377 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 497 of the PMS2 protein (p.Gly497Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs199739859, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals with colorectal cancer (PMID: 25559809) and endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 127761). 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 tolerated, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121849 SCV000601819 uncertain significance not specified 2016-09-09 criteria provided, single submitter clinical testing

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