Submissions for variant NM_000546.6(TP53):c.920-1G>T

dbSNP: rs587781702

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563356	SCV000664442	pathogenic	Hereditary cancer-predisposing syndrome	2017-06-06	criteria provided, single submitter	clinical testing	The c.920-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 8 of the TP53 gene. This altetation, designated as IVS8-1G>T, has been reported in a family that met Chompret criteria (Gonzalez KD et al. J. Med. Genet., 2009 Oct;46:689-93). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553698	SCV001774660	pathogenic	Li-Fraumeni syndrome	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.920-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: 4/4 predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251470 control chromosomes (gnomAD). c.920-1G>T has been reported in the literature in multiple families/individuals affected with tumors belonging to the Li-Fraumeni Syndrome tumor spectrum (e.g. Gonzalez_2009, Wu_2011, Rana_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000563356	SCV002582443	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289799	SCV002583105	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785455	SCV000924027	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV001672879	SCV001890922	not provided	not provided		no assertion provided	research