Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001806025 | SCV002052580 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-01-19 | criteria provided, single submitter | clinical testing | This variant causes an A to T nucleotide substitution at the -264 position of intron 15 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study showed that this variant resulted in two out-of-frame splicing defective transcripts that accounted for approximately 65% of variant transcripts (PMID: 31843900). This variant has been reported in two siblings affected with colon cancer with tumor sample from one carrier that showed the loss of MLH1 and PMS2 by immunohistochemistry (PMID: 31843900). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Ambry Genetics | RCV001806025 | SCV005448428 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-12-06 | criteria provided, single submitter | clinical testing | The c.1732-264A>T intronic variant results from an A to T substitution 264 nucleotides upstream from coding exon 16 in the MLH1 gene. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MLH1 expression by immunohistochemistry (IHC) (Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Ambry internal data). This variant was also identified in a proband diagnosed with colon cancer at age 31 that demonstrated loss of MLH1 and PMS2 expression on immunohistochemistry (IHC) and her brother was also diagnosed with colon cancer at age 42 (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec;116:26798-26807). RNA studies demonstrated abnormal splicing associated with this variant resulting from the creation of a cryptic donor splice site (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec;116:26798-26807). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| King Laboratory, |
RCV001171464 | SCV001251375 | pathogenic | Familial colorectal cancer; Lynch syndrome | 2019-09-01 | no assertion criteria provided | research |