Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
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) |
| Ambry Genetics | RCV002399442 | SCV002708429 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-20 | criteria provided, single submitter | clinical testing | The c.1668-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 15 in the MLH1 gene. This variant has been reported in a female diagnosed with endometrial cancer at age 48, rectal cancer at age 56, and three colon cancers at ages 63, 65, and 67. One colon tumor was MSI-H and exhibited loss of MLH1 on immunohistochemistry. Family history consisted of colorectal cancer in two relatives, endometrial cancer, and breast cancer (Dieumegard B et al. Br. J. Cancer, 2000 Feb;82:871-80). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
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. |