Submissions for variant NM_000546.6(TP53):c.919+1G>A

dbSNP: rs1131691039

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991150	SCV001142564	pathogenic	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.919+1G>A is a TP53 variant within the canonical donor site of exon 8. This change is observed to produce aberrant transcripts encoding premature truncations predicted to induce nonsense-mediated decay. (PVS1 (RNA); PMID: 17066464, 31092812). This variant has been reported in 1 proband meeting Classic criteria and 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points (PS4_Moderate; PMIDs: 29324801, 31081129, 20805372, ClinVar SCV001382474). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, ClinVar SCV001382474). This variant is absent from gnomAD v3.1.2 (non-cancer) and gnomAD v2.1.1 (non-cancer) (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PP4_Moderate, PS4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991150	SCV001382474	pathogenic	Li-Fraumeni syndrome	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 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 Li-Fraumeni syndrome (PMID: 20805372, 29070607, 29324801). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 633606). 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	RCV003307417	SCV003998799	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	The c.919+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the TP53 gene. This alteration has been reported in families meeting classic Li Fraumeni syndrome criteria and/or Chompret criteria for LFS (Marcel V et al. J Med Genet, 2009 Nov;46:766-72; Wilson JR et al. J Med Genet, 2010 Nov;47:771-4; Wong ESY et al. NPJ Genom Med, 2016 Jan;1:15003; Aceto GM et al. Breast Cancer Res Treat, 2019 Jun;175:479-485; Haque MM et al. Sci Rep, 2018 Aug;8:11705; Stoltze U et al. PLoS One, 2018 Jan;13:e0190050). This alteration has also been reported as a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (O'Shea R et al. Fam Cancer, 2018 Jan;17:123-128). 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. 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003992389	SCV004809802	pathogenic	Adrenocortical carcinoma, hereditary	2024-04-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000782136	SCV004933174	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000991150	SCV005685077	pathogenic	Li-Fraumeni syndrome	2025-01-10	criteria provided, single submitter	clinical testing	The following ACMG criteria was used: PVS1, PP4_MOD, PS4_MOD, PM2_SUP.
Academic Center for Education, Culture and Research, Motamed Cancer Institute	RCV000782136	SCV000914200	pathogenic	Li-Fraumeni syndrome 1	2019-05-21	no assertion criteria provided	clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001578272	SCV001805840	not provided	not provided		no assertion provided	in vivo
Clinical Genetics and Genomics, Karolinska University Hospital	RCV004797621	SCV005419167	pathogenic	TP53-related disorder	2024-10-01	no assertion criteria provided	clinical testing