Submissions for variant NM_000546.6(TP53):c.375+1G>A

dbSNP: rs1567555445

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Labcorp Genetics (formerly Invitae), Labcorp	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000786839	SCV002551080	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001021044	SCV002582405	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002290031	SCV002583067	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785320	SCV000923888	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786839	SCV000925735	not provided	not provided		no assertion provided	in vitro