Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Myriad Genetics, |
RCV002289931 | SCV004930497 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-13 | 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. |
| Genome- |
RCV002289931 | SCV002583061 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV001021043 | SCV002582399 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001591410 | SCV001823903 | likely pathogenic | not provided | 2024-02-07 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 17224268); This variant is associated with the following publications: (PMID: 17224268, 15510160) |
| Ambry Genetics | RCV001021043 | SCV001182606 | pathogenic | Hereditary cancer-predisposing syndrome | 2026-01-27 | criteria provided, single submitter | clinical testing | The c.375+1dupG intronic pathogenic mutation, results from the duplication of one nucleotide at nucleotide position 375 after intron 3 of the TP53 gene. This alteration was reported in an individual with breast cancer at 34 years of age who has a family member with sarcoma (Manoukian S et al. Eur. J. Cancer, 2007 Feb;43:601-6). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. This prediction is supported by preliminary RNA evidence (Ambry internal data). Another alteration at this same splice donor site (c.375+1G>A) has been reported in a family with early-onset bilateral breast cancer, leukemia, and a CNS tumor as well as in a female patient diagnosed with adrenal cortical carcinoma at age 11 months (Frebourg T et al. Am J Hum Genet. 1995 Mar;56(3):608-15; Pinto EM et al. Nat Commun. 2015 Mar 6;6:6302). Variants 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 variant is classified as a disease-causing mutation. |
| Labcorp Genetics |
RCV000633375 | SCV000754597 | pathogenic | Li-Fraumeni syndrome | 2025-06-01 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 4 of the TP53 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 TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 7887414, 17224268; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 528263). 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. |