ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2523G>A (p.Trp841Ter) (rs587780057)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586246 SCV000697349 uncertain significance not specified 2019-06-17 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2523G>A (p.Trp841X) results in a premature termination codon in the last exon of the PMS2 mRNA, which raises the possibility of it escaping nonsense mediated decay and causing a truncation of the last 22 amino acids (Trp841-Asn862) of the PMS2 protein. The variant allele was found at a frequency of 0.00039 in 180738 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 3.5 fold above the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), suggesting that the variant is benign. However, the region is highly homologous to PMS2 pseudogenes, and the technology utilized for this dataset does not rule out pseudogene interference making ExAC and gnomAD data unreliable for assessing variant frequency. c.2523G>A has been reported in the literature in individuals affected with HBOC and other cancer types. Since none of these reports ruled out PMS2 pseudogene interference, these reports do not provide unequivocal conclusions about an association of the variant with Lynch Syndrome. A co-occurrence with a pathogenic variant has been reported (PALB2 c.3323delA; LabCorp internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Of note however, in functional studies performed on lymphoblastoid cell lines (LCLs) derived from a patient carrying a similar truncating variant (c.2521delT (p.Trp841GlyfsX10)) in homozygosity, MSI (microsatellite instability) and tolerance to methylating agents could be demonstrated (PMID: 26116798). These results suggest that truncation of the last 22 amino acids might have functional importance. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000708976 SCV000838164 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000987818 SCV001137276 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing

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