ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs143235330
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Total submissions: 7
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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 2023-07-24 criteria provided, single submitter clinical testing The p.D526G variant (also known as c.1577A>G), located in coding exon 11 of the PMS2 gene, results from an A to G substitution at nucleotide position 1577. The aspartic acid at codon 526 is replaced by glycine, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000462922 SCV000552030 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 526 of the PMS2 protein (p.Asp526Gly). This variant is present in population databases (rs143235330, gnomAD 0.03%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 34250417). ClinVar contains an entry for this variant (Variation ID: 187056). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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 2023-04-28 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with a personal or family history suspicious for Lynch syndrome (Pearlman et al., 2021); This variant is associated with the following publications: (PMID: 34250417, 34680378)
Color Diagnostics, LLC DBA Color Health RCV000166743 SCV000911417 likely benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780624 SCV000918052 uncertain significance not specified 2022-10-26 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1577A>G (p.Asp526Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251068 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1577A>G has been reported in the literature in an individual affected with Colorectal Cancer without evidence of causality (Pearlman_2021). This report does 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five laboratories classified it as uncertain significance and one likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000780624 SCV002069659 uncertain significance not specified 2020-12-31 criteria provided, single submitter clinical testing DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1577A>G, in exon 11 that results in an amino acid change, p.Asp526Gly. This sequence change does not appear to have been previously described in patients with PMS2-related disorders and has been described in the gnomAD database with a frequency of 0.032% in the African sub-population (dbSNP rs143235330). The p.Asp526Gly change affects a poorly conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. The p.Asp526Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp526Gly change remains unknown at this time.
Sema4, Sema4 RCV000166743 SCV002530207 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-07 criteria provided, single submitter curation

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