Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV001187196 | SCV001353925 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-02-06 | criteria provided, single submitter | clinical testing | This variant causes a G>A nucleotide substitution at the +1 position of intron 7 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with lobular breast cancer (PMID: 23709761). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |
Ambry Genetics | RCV001187196 | SCV004057713 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-12 | criteria provided, single submitter | clinical testing | The c.1008+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the CDH1 gene. This alteration has been reported in an individual affected with lobular breast cancer (Benusiglio PR et al. J Med Genet, 2013 Jul;50:486-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |