ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1730dup (p.Arg578fs) (rs587779330)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076822 SCV000108309 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000076822 SCV000552001 pathogenic Lynch syndrome 2016-11-28 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 11 of the PMS2 mRNA (c.1730dupA), causing a frameshift at codon 578. This creates a premature translational stop signal (p.Arg578Alafs*3) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic. This particular variant has been reported in the literature in two siblings affected with constitutional mismatch repair deficiency (CMMR-D) associated tumors, who also carried a second pathogenic PMS2 variant in trans as well as an adjacent nucleotide substitution c.1732C>T in cis (PMID: 17557300). It has also been reported in an individual with colorectal cancer (PMID: 22585707). In these affected individuals, this variant was shown to be derived from the PMS2CL pseudogene by a gene conversion event (PMID: 17557300, 22585707). Expression analysis has shown that patient-derived lymphocytes carrying this variant did not express the PMS2 protein (PMID: 17557300). For these reasons, this variant has been classified as Pathogenic.

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