ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000123081 SCV000166377 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115659 SCV000186706 likely benign Hereditary cancer-predisposing syndrome 2018-05-21 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121849 SCV000601819 uncertain significance not specified 2016-09-09 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
GeneKor MSA RCV000115659 SCV000822122 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000115659 SCV000902676 likely benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
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.
Mendelics RCV000663092 SCV001137296 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000663092 SCV001322472 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ITMI RCV000121849 SCV000086049 not provided not specified 2013-09-19 no assertion provided reference population

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