ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.989-2A>G (rs587779347)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076905 SCV000108403 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000132347 SCV000187436 pathogenic Hereditary cancer-predisposing syndrome 2018-11-27 criteria provided, single submitter clinical testing The c.989-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 10 in the PMS2 gene. This mutation has been reported in an individual diagnosed with colon cancer at age 72 whose tumor showed high microsatellite instability and a loss of PMS2 on IHC. Both affected and unaffected family members were found to carry this mutation (Borras E et al. J Med Genet. 2013 Aug;50(8):552-63). This mutation has also been reported in an individual diagnosed with two primary early onset breast cancers and having a family history of bilateral breast cancer, endometrial cancer, and small intestinal cancer (Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). Further studies showed that this mutation lead to in-frame skipping of coding exon 10 (Borras E et al. J Med Genet. 2013 Aug;50(8):552-63; van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3:327-45; Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000531809 SCV000625713 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-15 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 in families affected with Lynch syndrome (PMID: 23709753, 26110232). ClinVar contains an entry for this variant (Variation ID: 91386). Experimental studies have shown that this splice site change results in the in-frame skipping of exon 10 (PMID: 26247049, 23709753). 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.
Color Health, Inc RCV000132347 SCV001339644 pathogenic Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV001523837 SCV001478144 likely pathogenic Mismatch repair cancer syndrome 4 2020-12-15 criteria provided, single submitter research
GeneDx RCV001556367 SCV001777937 pathogenic not provided 2019-04-16 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region [Part of the ATPase domain]; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31992580, 30306255, 21376568, 25512458, 26110232, 23709753, 26247049, 24362816)

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