Submissions for variant NM_000546.6(TP53):c.673-1G>C

dbSNP: rs878854073

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873819	SCV002243451	pathogenic	Li-Fraumeni syndrome	2024-04-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 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 individual(s) with breast cancer, clinical features of Li-Fraumeni syndrome, and/or hereditary cancer syndrome (PMID: 11370630, 27621308, 31159747, 34196900; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1228368). 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	RCV003298947	SCV003995355	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	The c.673-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 6 of the TP53 gene. 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; however, direct evidence is insufficient at this time (Ambry internal data). Another alteration impacting the same acceptor site (c.673-2A>G) has been described in individuals with a personal and/or family history that is consistent with TP53-related disease (Jhaveri AP et al. Yale J Biol Med, 2015 Jun;88:181-5; Heymann S et al. Radiat Oncol, 2010 Nov;5:104). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Color Diagnostics, LLC DBA Color Health	RCV003298947	SCV004359992	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 6 of the TP53 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. Other variants at this position have been observed in Li Fraumeni patients and classified as Pathogenic (ClinVar Variation IDs: 237953, 379336). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV004039541	SCV004930515	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-15	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.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001614459	SCV001837605	not provided	not provided		no assertion provided	in vivo