Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV003117344 | SCV007449421 | pathogenic | Li-Fraumeni syndrome | 2023-04-10 | criteria provided, single submitter | clinical testing | This variant is predicted to result in loss of function through nonsense-mediated decay of the encoded transcript or premature truncation of the encoded protein in a gene in which loss of function is a known mechanism of disease (ACMG/AMP: PVS1). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1_Supporting). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2_Supporting). |
| Myriad Genetics, |
RCV003338668 | SCV004933301 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-21 | 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. |
| Neuberg Centre For Genomic Medicine, |
RCV003338668 | SCV004048548 | pathogenic | Li-Fraumeni syndrome 1 | criteria provided, single submitter | clinical testing | The splice acceptor c.994-2A>G variant has been reported previously in heterozygous state in patients affected with Li-Fraumeni syndrome (Bachinski, E. et. al., 2005).The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant mutates a splice-acceptor sequence, potentially resulting in exon skipping and the production of abnormal proteins. This variant has been reported to the ClinVar database as Likely Pathogenic. The nucleotide change in TP53 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. | |
| Labcorp Genetics |
RCV003117344 | SCV003787078 | pathogenic | Li-Fraumeni syndrome | 2026-01-25 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 9 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: 10980596, 12610779, 20522432, 26014290, 26911350). ClinVar contains an entry for this variant (Variation ID: 487000). RNA analysis provides insufficient evidence to determine the effect of this variant on TP53 splicing (internal data). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000572283 | SCV000676298 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-04 | criteria provided, single submitter | clinical testing | The c.994-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the TP53 gene. This alteration occurs at the 3' terminus of the TP53 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 35 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Two other alterations impacting the same acceptor site (c.994-1G>C and c.994-1G>A) have been shown to have an impact on splicing and have been reported in individuals with Li-Fraumeni syndrome (Verselis SJ, et al. Oncogene. 2000 Aug; 19(37):4230-5; Hwang SJ et al. Am J Hum Genet. 2003 Apr;72(4):975-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Dr. |
RCV005898534 | SCV006897651 | not provided | Ovarian serous cystadenocarcinoma | no classification provided | in vitro | ||
| Dr. |
RCV005898532 | SCV006897650 | not provided | Hepatocellular carcinoma | no classification provided | in vitro | ||
| Dr. |
RCV005898533 | SCV006897649 | not provided | Malignant lymphoma, large B-cell, diffuse | no classification provided | in vitro | ||
| Clinical Genetics and Genomics, |
RCV004797615 | SCV005419169 | likely pathogenic | TP53-related disorder | 2024-10-01 | no assertion criteria provided | clinical testing | |
| Mut |
RCV000786813 | SCV000925705 | not provided | not provided | no classification provided | in vitro |