Submissions for variant NM_000546.6(TP53):c.672+1G>A

dbSNP: rs863224499

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200333	SCV000253850	pathogenic	Li-Fraumeni syndrome	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the TP53 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the gain of 6 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 16494995, 23409989, 29070607; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 216078). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects TP53 function (PMID: 22495821). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 6 (PMID: 22495821, 23409989). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000786828	SCV002559557	pathogenic	not provided	2022-08-02	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of transcriptional activity, reduced cell cycle check point arrest in comparison to wild type (Piao et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one case of pediatric osteosarcoma in an individual with a family history consistent with Li-Fraumeni like syndrome (Sakurai et al., 2013); This variant is associated with the following publications: (PMID: 22495821, 22911296, 23409989, 16494995, 27352257, 25149524, 27614696, 22703554, 30720243)
Genome-Nilou Lab	RCV002288814	SCV002582476	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288813	SCV002583137	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002288814	SCV003911996	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	The c.672+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the TP53 gene. This variant has been reported in an individual with osteosarcoma diagnosed at age 15 (Sakurai N et al. Pediatr Int, 2013 Feb;55:107-11). Functional studies performed on this variant include RNA analysis which identified an 18 nucleotide insertion event and functional studies which demonstrated loss of function (Piao J et al. Mol Carcinog, 2013 Oct;52:770-6). 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 donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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.
Baylor Genetics	RCV003474954	SCV004204265	pathogenic	Adrenocortical carcinoma, hereditary	2022-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002288814	SCV004359993	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the +1 position of intron 6 of the TP53 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant may result in the use of a cryptic donor site 18 base pairs into intron 6, resulting in the insertion of 6 amino acids into the DNA binding domain (PMID: 23409989). Functional studies using this 6 amino acid construct showed impaired TP53 transcriptional transactivation, reduced cell cycle arrest at G0/G1 in response to DNA damage, and impaired ability to inhibit cell growth (PMID: 22495821). This variant has been reported in individuals affected with osteosarcoma and rhabdomyosarcoma, the latter of which was confirmed de novo (PMID: 22495821, 23409989, 29070607). 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. Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV002288813	SCV004932263	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	RCV000786828	SCV000925722	not provided	not provided		no assertion provided	in vitro