Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002031560 | SCV002312430 | uncertain significance | Li-Fraumeni syndrome | 2022-07-26 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1524222). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the TP53 gene. It does not change the encoded amino acid sequence of the TP53 protein. It affects a nucleotide within the consensus splice site. |
| Ambry Genetics | RCV002441237 | SCV002752350 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-10-05 | criteria provided, single submitter | clinical testing | The c.-29+1G>C intronic variant is located in the 5' untranslated region (5’ UTR) of the TP53 gene. This intronic variant results from a G to C substitution one nucleotide after the first non-coding exon. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). Another variant impacting the same splice site, TP53 c.-29+1G>T, was identified in a family with Li Fraumeni Syndrome (Verselis SJ et al. Oncogene, 2000 Aug;19:4230-5). Further analyses of this variant did not detect any abnormally spliced transcript; however only transcripts from one allele were observed, suggesting monoallelic expression of the TP53 transcript. 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. RNA studies did not detect abnormal splicing in the set of samples tested; however additional analyses indicated the presence of transcripts from only one allele, as described for TP53 c.-29+1G>T (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |