ClinVar Miner

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

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Total submissions: 12
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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 2020-12-03 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 Health, Inc RCV000115659 SCV000902676 likely benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121849 SCV000920047 likely benign not specified 2021-01-28 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 allele was found at a frequency of 0.00012 in 251416 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1490G>A has been reported in the literature in individuals affected with various types of cancers including but not limited to rectal cancer, colorectal cancer, epithelial ovarian cancer, pancreatic cancer and hereditary breast and ovarian cancer (example: Chubb_2015, Ring_2016, Krivokuca_2019, Young_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=3) or uncertain significance (n=9). Based on the evidence outlined above, the variant was classified as likely benign.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354802 SCV001549503 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Gly497Asp variant was identified in 2 of 2014 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer or endometrial carcinoma (Chubb 2015, Ring 2016). The variant was also identified in the following databases: dbSNP (ID: rs199739859) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by GeneDx, Invitae, and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, Cosmic (1x in central nervous system), and Insight Hereditary Tumors database. The variant was not identified in the COGR, MutDB, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant databases. The variant was identified in control databases in 33 of 277164 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 3 of 34420 chromosomes (freq: 0.0001), European in 27 of 126690 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10148 chromosomes (freq: 0.0001); but not in the African, East Asian, Finnish, and South Asian populations. The p.Gly497 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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