Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Diagnostics Laboratory, |
RCV001021044 | SCV005901771 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-12-18 | criteria provided, single submitter | clinical testing | PVS1 (RNA), PS2, PM2_Supporting c.375+1G>A, located in a canonic splicing site of the TP53 is predicted to alter splicing. The SpliceAI algorithm predicts that the variant disrupts the adjacent canonical donor site (deltascore=0.98) and activates at least two cryptic splice donor sites: an intronic donor 47 nucleotides upstream (deltascore=0.21) and one exonic donor 201 nucleotides dowstream (deltascore=0.20)(allways referring to the variant, in coding sequence sense, which is contrary to the genomic one). Two RNA studies (a cDNA transfection assay,PMID: 34675114, and RNAseq data from a tumor carrying the variant in homo/hemizygosis, MutSpiceDB) show splicing alterations, the main effects observed are the retention of the whole intron 4 and the partial skipping of the last 200 bp of exon 4 (this one predicted by SpliceAI). Both alterations are predicted to cause a frameshift with premature protein truncation and nonsense mediated decay (PVS1 (RNA)). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_Supporting). In addition, it was identified ClinVar database (2x pathogenic; 5x likely pathogenic) but it has not been reported in the LOVD database. This variant has been reported as de novo in an individual (1 year old) with adrenocortical carcinoma and maternity and paternity are confirmed (PMID: 34675114) and reported as TP53 mosaic variant in a patient with osteosarcoma (at 12 years) and breast carcinoma and breast sarcoma (at 35 years)(PS2). Based on currently available information, c.375+1G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 2.2. |
| Myriad Genetics, |
RCV002290031 | SCV004930568 | 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- |
RCV002290031 | SCV002583067 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV001021044 | SCV002582405 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV000786839 | SCV002551080 | pathogenic | not provided | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001385498 | SCV001585376 | pathogenic | Li-Fraumeni syndrome | 2025-01-06 | criteria provided, single submitter | clinical testing | This sequence change affects a donor 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 Li-Fraumeni syndrome (PMID: 7887414, 17224268, 29070607). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 634702). 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 | RCV001021044 | SCV001182607 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-08-19 | criteria provided, single submitter | clinical testing | The c.375+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the TP53 gene. This alteration 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). This alteration has also been reported as mosaic in a French proband diagnosed with osteosarcoma at 12 years and bilateral breast cancer at 35 years (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180). 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; however, direct evidence is insufficient at this time (Ambry internal data). 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 likely pathogenic. |
| Mut |
RCV000786839 | SCV000925735 | not provided | not provided | no assertion provided | in vitro | ||
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785320 | SCV000923888 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |