ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.989-1G>T (rs587780064)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115713 SCV000149622 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.989-1G>T or IVS9-1G>T and consists of a G>T nucleotide substitution at the -1 position of intron 9 of the PMS2 gene. The variant destroys a canonical splice acceptor site and causes abnormal gene splicing. RT-PCR analysis and a minigene assay have demonstrated that the variant leads to whole or partial in-frame deletion of exon 10 which includes part of the ATPase domain (Sjursen 2009, Fukui 2011, van der Klift 2015). This variant was first identified in the homozygous state in a sibling pair, one with glioblastoma and two colon cancers by age 20 and the other with colon cancer at age 19 (Sjursen 2009). The variant has since been reported as a Norwegian pathogenic founder variant in hereditary colorectal cancer families (Sjursen 2010, Grindedal 2014). Grindedal et al. (2014) reported that the majority of tumors tested showed normal PMS2 protein expression by IHC but most demonstrated microsatellite instability. The authors calculated a high probability of pathogenicity (>0.99) based on segregation analysis and reported age-specific penetrance estimates for carriers of this variant (Grindedal 2014). It is important to note that such penetrance estimates are based on a small cohort of patients. Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000563759 SCV000663469 pathogenic Hereditary cancer-predisposing syndrome 2019-05-20 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Color RCV000563759 SCV000686265 pathogenic Hereditary cancer-predisposing syndrome 2016-09-09 criteria provided, single submitter clinical testing
Invitae RCV000697325 SCV000825927 pathogenic Hereditary nonpolyposis colon cancer 2018-12-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous in an individual affected with Turcot syndrome (PMID: 19039682) and reported to segregate with Lynch syndrome in several families in the Norwegian populations (PMID: 19039682, 24790682, 19723918). ClinVar contains an entry for this variant (Variation ID: 127802). Experimental studies using patient RNA and splicing report minigene assay have shown that this missense change results in skipping of exon 10 (PMID: 19039682, 26247049). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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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