Submissions for variant NM_000546.6(TP53):c.782+1G>T

dbSNP: rs1555525429

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587342	SCV000697447	likely pathogenic	Li-Fraumeni syndrome	2016-12-22	criteria provided, single submitter	clinical testing	Variant summary: The TP53 c.782+1G>T variant involves the alteration of a conserved intronic nucleotide. Mutation taster predicts a damaging outcome for this variant along with 5/5 splice prediction tools predicting the variant to have an impact on normal splicing. The variant is absent in 121174 control chromosomes and to our knowledge, it was not reported in affected individuals with Li-Fraunemi syndrome, although several reports of its occurrence as a somatic driver mutation in patients with a wide variety of cancers such as osteosarcoma, breast cancer, thymic carcinoma and small cell lung carcinoma have been described. Taken together, this variant is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV004024677	SCV004930421	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-20	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.
Ambry Genetics	RCV004678753	SCV005177913	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-27	criteria provided, single submitter	clinical testing	The c.782+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 6 of the TP53 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well 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. As such, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000587342	SCV005839576	pathogenic	Li-Fraumeni syndrome	2024-11-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 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 breast cancer (PMID: 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 496048). 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.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785462	SCV000924034	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786822	SCV000925715	not provided	not provided		no assertion provided	in vitro