ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1668-3C>A (rs267607844)

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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) RCV000075303 SCV000106299 likely pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Exon 15 skipping shown in minigene & RT-PCR & possibly 2 MSI tumours (1 from Dieumegard et al 2000 & 1 from UMD)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503705 SCV000592415 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The c.1668-3C>A variant has been reported in the literature in 1/68 proband chromosomes of an individual with incomplete HNPCC. This patient showed a strong family history of CRC, but was missing at least one HNPCC criterion. The variant was not found in any of the 192 control chromosomes tested. The tumor from this patient was MSI positive, lacked IHC MLH1 staining, and was found to exhibit LOH (Dieumegard_2000_10732761). The variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing, increasing the likelihood that this variant has clinical significance Computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 2 of 5 different programs. However, this information is not predictive enough to rule out pathogenicity. In summary, based on above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a Variant of Unknown Significance.

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