Submissions for variant NM_000546.6(TP53):c.920-2A>G

dbSNP: rs397516439

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132190	SCV000187270	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-05-15	criteria provided, single submitter	clinical testing	The c.920-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 8 in the TP53 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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.
GeneDx	RCV000483617	SCV000571425	pathogenic	not provided	2018-08-24	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.920-2A>G or IVS8-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 8 of the TP53 gene. This variant destroys a canonical splice site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Although this variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant, other variants impacting the same splice site have been reported in association with Li-Fraumeni syndrome (Gonzalez 2009, Wu 2011). Based on the current available evidence, we consider TP53 c.920-2A>G to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000036537	SCV001224140	pathogenic	Li-Fraumeni syndrome	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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 individuals with clinical features of Li-Fraumeni syndrome (PMID: 19556618, 21305319, 32817165; Invitae). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 43595). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000483617	SCV001474488	pathogenic	not provided	2019-08-07	criteria provided, single submitter	clinical testing	The TP53 c.920-2A>G variant (rs397516439) is reported in the literature in colon cancer, thyroid cancer, lung cancer, and ovarian cancer specimens (Grassi 2015, Kandioler 2015, Lee 2010, Wojnarowicz 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 43595). This variant abolishes the canonical splice acceptor site of intron 8, which is likely to disrupt gene function. Other variants that abolish the same splice acceptor site (c.920-1G>A, c.920-1G>T) have been reported in individuals with symptoms or diagnoses of Li-Fraumeni syndrome, suggesting that disruption of this splice site is associated with disease (Gonzalez 2009, Wu 2011). Based on available information, the c.920-2A>G variant is considered to be pathogenic. References: Gonzalez KD et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet. 2009 Oct;46(10):689-93. Grassi ES et al. SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways. Oncotarget. 2015 Nov 3;6(34):36383-99. Kandioler D et al. TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients. EBioMedicine. 2015 Jun 8;2(8):825-30. Lee EB et al. TP53 mutations in Korean patients with non-small cell lung cancer. J Korean Med Sci. 2010 May;25(5):698-705. Wojnarowicz PM et al. The genomic landscape of TP53 and p53 annotated high grade ovarian serous carcinomas from a defined founder population associated with patient outcome. PLoS One. 2012;7(9):e45484. Wu CC et al. Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. Hum Genet. 2011 Jun;129(6):663-73.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798102	SCV002042837	likely pathogenic	Breast and/or ovarian cancer	2020-03-24	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000132190	SCV002582340	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288536	SCV002583002	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288536	SCV004930900	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036537	SCV000060192	likely pathogenic	Li-Fraumeni syndrome	2008-08-01	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785489	SCV000924061	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000483617	SCV001762396	not provided	not provided		no assertion provided	in vivo