ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.208-3C>G (rs267607720)

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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) RCV000075517 SCV000106518 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Variant causes splicing aberration (not quantified) & 3 MSI-H tumours. Multifactorial likelihood analysis posterior probability 0.95-0.99.
GeneDx RCV000160554 SCV000211132 likely pathogenic not provided 2019-10-28 criteria provided, single submitter clinical testing Intronic variant demonstrated to result in an in-frame deletion of exon 3 (Arnold 2009); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25525159, 26681312, 25980754, 28765196, 15991306, 19267393)
Invitae RCV000524274 SCV000284047 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-06-12 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with Lynch syndrome and colon cancer, and was reported to segregate with disease in a family (PMID: 19267393, 15991306, 26681312). This variant is also known as IVS2-3C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 90032). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change results in the in-frame skipping of exon 3 in RNA derived from patient lymphoblastoid cells. In addition, the examination of tumor tissue from affected individuals with this variant has confirmed the presence of microsatellite instability and protein expression levels consistent with an MLH1 mutation (PMID: 19267393, 15991306). However, a direct effect of the skipping of this exon on protein function has not been demonstrated to date. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000562969 SCV000669543 pathogenic Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing The c.208-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 3 in the MLH1 gene. This alteration has been reported in multiple individuals with MLH1/PMS2-absent, microsatellite unstable, HNPCC-related tumors (Arnold S, Hum. Mutat. 2009 May; 30(5):757-70; Ambry internal data). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site and analysis of patient-derived RNA found that this alteration results in aberrant splicing leading to transcripts lacking coding exon 3 (Otway R, Hum. Genet. 2005 May; 116(6):535; Arnold S, Hum. Mutat. 2009 May; 30(5):757-70). This alteration co-segregates with HNPCC-related tumors in multiple families (Arnold S, Hum. Mutat. 2009 May; 30(5):757-70; Ambry internal data). This nucleotide position is poorly conserved in available vertebrate species. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington RCV000075517 SCV000887397 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.208-3C>G has a 97.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Fulgent Genetics,Fulgent Genetics RCV000763098 SCV000893640 likely pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing

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