ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1577A>G (p.Asp526Gly) (rs143235330)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166743 SCV000217554 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000462922 SCV000552030 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 526 of the PMS2 protein (p.Asp526Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs143235330, ExAC 0.04%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 187056). 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.
GeneDx RCV000483914 SCV000565414 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1577A>G at the cDNA level, p.Asp526Gly (D526G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAC>GGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Asp526Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Asp526Gly is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Asp526Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166743 SCV000911417 likely benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780624 SCV000918052 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1577A>G (p.Asp526Gly) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/276798 control chromosomes, observed exclusively in the African subpopulation at a frequency of 0.000293 (7/23898). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. A high homology pseudogene of PMS2 may complicate interpretation of NGS-derived control data. However, analysis of the sequence in the region surrounding the variant shows several differences between PMS2 and the pseudogene, which provides more confidence in the data. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign.

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