ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1379G>A (p.Gly460Asp) (rs150201462)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131270 SCV000186238 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000477201 SCV000551969 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 460 of the PMS2 protein (p.Gly460Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. While this variant is present in population databases (rs150201462), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with glioblastoma multiforme (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 142257). 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 aspartic acid amino acid residue is also 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. 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.
GeneDx RCV000767041 SCV000565823 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1379G>A at the cDNA level, p.Gly460Asp (G460D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant was observed in at least one individual with glioblastoma multiforme (Lu 2015). Although this variant was observed in large population cohorts, 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 Gly460Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000483100 SCV000592933 likely benign not specified 2015-01-28 criteria provided, single submitter clinical testing
Counsyl RCV000662638 SCV000785324 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-07-06 criteria provided, single submitter clinical testing
Color RCV000131270 SCV000911028 likely benign Hereditary cancer-predisposing syndrome 2016-09-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000483100 SCV000920023 uncertain significance not specified 2017-10-27 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1379G>A (p.Gly460Asp) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index; SIFT tool not functioning). This variant was found in 3/30966 control chromosomes at a frequency of 0.0000969, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). However, this site did not pass quality control filters in the gnomAD database and the presence of a high homology PMS2 pseudogene also complicates the interpretation of this control data. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000483100 SCV000967508 uncertain significance not specified 2018-10-16 criteria provided, single submitter clinical testing The p.Gly460Asp variant in PMS2 has not been reported in individuals with PMS2-a ssociated cancers, but has been reported by other clinical laboratories in ClinV ar (Variation ID: 142257). It has also been identified in 3/8728 African chromos omes by gnomAD ( Computational prediction tool s and conservation analysis suggest that the p.Gly460Asp variant may not impact the protein. In summary, the clinical significance of the p.Gly460Asp variant is uncertain. ACMG/AMP Criteria applied: BP4.

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