Submissions for variant NM_000546.6(TP53):c.673-2A>G

dbSNP: rs1555525585

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553068	SCV000629851	pathogenic	Li-Fraumeni syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 458555). Disruption of this splice site has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 21059199, 26029016). In at least one individual the variant was observed to be de novo.
GeneDx	RCV000786824	SCV001791642	pathogenic	not provided	2021-06-14	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in an abnormal protein product or nonsense mediated mRNA decay in a gene for which loss-of-function is a known mechanism of disease (Aspesi 2014, Senturk 2014); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28369373, 32658383, 26029016, 33063681, 31221207, 21059199, 27759562, 30720243, 25074920, 24835311, 25525159, 28472496)
Genome-Nilou Lab	RCV002289738	SCV002582475	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289737	SCV002583136	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002289738	SCV002667407	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	The c.673-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 6 in the TP53 gene. This mutation, referred to as IVS6-2A>G, was described in a female patient diagnosed with five primary cancers before the age of 30 whose parents tested negative for this mutation (Jhaveri AP et al. Yale J Biol Med, 2015 Jun;88:181-5). This mutation was also reported in a female patient with ductal carcinoma in situ at age 39 whose 18 year-old daughter had two sarcomas (Heymann S et al. Radiat Oncol, 2010 Nov;5:104). 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. Published RNA studies have suggested that this variant disrupts mRNA splicing (Aspesi A et al. Gene, 2014 Jul;545:282-9; Senturk S et al. Proc Natl Acad Sci U S A, 2014 Aug;111:E3287-96). 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 a disease-causing mutation.
Myriad Genetics, Inc.	RCV002289737	SCV004933424	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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785307	SCV000923875	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786824	SCV000925718	not provided	not provided		no assertion provided	in vitro