Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000230457 | SCV000284324 | pathogenic | Gorlin syndrome | 2023-09-19 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individuals with clinical features of basal cell nevus syndrome (PMID: 29575684; Invitae). This sequence change affects an acceptor splice site in intron 1 of the PTCH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 237465). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV001014123 | SCV001174798 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-09-25 | criteria provided, single submitter | clinical testing | The c.202-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the PTCH1 gene. This alteration has been reported in a cohort of patients referred for testing for nevoid basal cell carcinoma syndrome (NBCCS) (Reinders MG et al. Mol Genet Genomic Med. 2018 05;6:409-415). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. |
| Gene |
RCV002253306 | SCV002525368 | pathogenic | not provided | 2022-06-01 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29575684, 28328109) |
| St. |
RCV000230457 | SCV003842978 | uncertain significance | Gorlin syndrome | 2022-01-03 | criteria provided, single submitter | clinical testing | The PTCH1 c.202-2A>G intronic change results from an A to G substitution at the -2 position of intron 1 of the PTCH1 gene. This variant disrupts the native splice site at c.202 resulting in out-of-frame alternative splicing between exons 1 and 3 and skipping of exon 2. This variant has been reported in individuals with nevoid basal cell carcinoma syndrome (PMID: 29575684, 28328109). It has also been identified in an individual with a SHH-medulloblastoma with an increased variant allele frequency in the tumor (internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. |