ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.325dup (p.Glu109fs) (rs587781716)

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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 RCV000218863 SCV000277647 pathogenic Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Color RCV000218863 SCV000909678 pathogenic Hereditary cancer-predisposing syndrome 2017-11-22 criteria provided, single submitter clinical testing
GeneDx RCV000657178 SCV000778899 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing This duplication of one nucleotide in PMS2 is denoted c.325dupG at the cDNA level and p.Glu109GlyfsX30 (E109GfsX30) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CGGGGG[dupG]AAGC. The duplication causes a frameshift, which changes a Glutamic Acid to a Glycine at codon 109, and creates a premature stop codon at position 30 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been identified in multiple individuals with a personal and/or family history of colon cancer, one of whom was diagnosed with an early onset colorectal tumor that demonstrated absence of PMS2 on immunohistochemistry (IHC) (Vaughn 2010, Suerink 2015, Goodenberger 2016). It has also been reported in at least one individual with constitutional mismatch repair deficiency (CMMR-D) in whom a second PMS2 variant had been identified on the opposite allele (in trans) (Johannesma 2011). Minigene and patient-derived cell line RNA analyses suggest this variant may be associated with a shift towards expression of alternative out-of-frame transcripts that are subjected to NMD (van der Klift 2015). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709752 SCV000840044 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-05-11 criteria provided, single submitter clinical testing This c.325dup (p.Glu109Glyfs*30) variant has been reported in a cohort of 145 unrelated patients with colorectal cancer [PMID 20205264]. This variant has been observed in 3 heterozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/7-6043348-T-TC). This 1bp duplication creates a frameshift and is predicted to create a premature stop codon 30 amino acid downstream, and to result in a loss of function of the PMS2 protein. This variant is thus classified as pathogenic.
Invitae RCV000536196 SCV000625635 pathogenic Hereditary nonpolyposis colon cancer 2018-06-01 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 4 of the PMS2 mRNA (c.325dupG), causing a frameshift at codon 109. This creates a premature translational stop signal (p.Glu109Glyfs*30) and is expected to result in an absent or disrupted protein product. This variant has been reported in the literature in an individual affected with colorectal cancer and in a family affected with constitutional mismatch repair deficiency (PMID: 20205264, 21261604). ClinVar contains an entry for this variant (Variation ID: 233300). Experimental studies have shown that this insertion causes out-of-frame exon skipping in a minigene assay (PMID: 26247049). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.

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