ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1798A>G (p.Met600Val) (rs1304634005)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000662640 SCV000785326 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000772030 SCV000904998 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-26 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 600 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000772030 SCV001173766 likely benign Hereditary cancer-predisposing syndrome 2019-05-22 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030721 SCV001193689 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Invitae RCV001061729 SCV001226482 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-09 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 600 of the PMS2 protein (p.Met600Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 548758). 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 valine 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358228 SCV001553902 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PMS2 p.Met600Val variant was identified in 1 of 1144 proband chromosomes (frequency: 0.0009) from individuals or families with atherosclerosis (Johnston 2012,). The variant was identified in dbSNP (rs1304634005) as “NA” and ClinVar (classified as uncertain significance by Color and Counsyl). The variant was identified in control databases in 2 of 251,454 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 1 of 10,078 chromosomes (freq: 0.0001) and East Asian in 1 of 18,394 chromosomes (freq: 0.00005), while it was not observed in the African, Latino, Finnish, European, Other or South Asian populations. The p.Met600 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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