Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076349 | SCV000107375 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Color Diagnostics, |
RCV000774579 | SCV000908323 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-01-02 | criteria provided, single submitter | clinical testing | This variant causes an A to G nucleotide substitution at the canonical -2 position of intron 12 splice acceptor site of the MSH2 gene. This variant has been reported in an individual affected with Lynch syndrome with multiple primary tumors (PMID: 17250671). This variant has also been observed de novo in a young female affected with Lynch syndrome (PMID: 19047842). RNA studies using cells from these individuals have shown that this variant causes out-of-frame skipping of exon 13, resulting in a premature protein truncation (PMID: 17250671, 19047842). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420710 | SCV000917706 | pathogenic | Hereditary nonpolyposis colon cancer | 2021-05-05 | criteria provided, single submitter | clinical testing | Variant summary: MSH2 c.2006-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon 13 skipping (example, Ding_2007). The variant was absent in 251336 control chromosomes. c.2006-2A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (example, Ding_2007, Morak_2017, Parc_2003). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Myriad Genetics, |
RCV003452877 | SCV004186646 | likely pathogenic | Lynch syndrome 1 | 2023-08-04 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. |
| Baylor Genetics | RCV003452877 | SCV004196937 | pathogenic | Lynch syndrome 1 | 2021-05-25 | criteria provided, single submitter | clinical testing |