ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1438G>C (p.Gly480Arg) (rs146848345)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129313 SCV000184075 benign Hereditary cancer-predisposing syndrome 2012-10-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000216564 SCV000274612 uncertain significance Tumor susceptibility linked to germline BAP1 mutations 2015-03-24 criteria provided, single submitter clinical testing
GeneDx RCV000589892 SCV000279140 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1438G>C at the cDNA level, p.Gly480Arg (G480R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>CGA). This variant has been identified in at least one individual undergoing multigene cancer panel testing (Yorczyk 2014). Although PMS2 Gly480Arg 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 information, it is unclear whether PMS2 Gly480Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589892 SCV000697297 uncertain significance not provided 2017-02-03 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1438G>C (p.Gly480Arg) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant was reported in the literature in a patient being tested for HBOC or Lynch Syndrome, without strong evidence for causality (Yorczyk_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as VUS.
Invitae RCV000629794 SCV000750750 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 480 of the PMS2 protein (p.Gly480Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs146848345, ExAC 0.001%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 141000). 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.
Color RCV000129313 SCV000911857 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing

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