Submissions for variant NM_000546.6(TP53):c.375+2T>C

dbSNP: rs1555526469

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505908	SCV000602268	likely pathogenic	not provided	2017-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586625	SCV000697441	likely pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-14	criteria provided, single submitter	clinical testing	Variant summary: The TP53 c.375+2T>C variant involves the alteration of a highly conserved intronic nucleotide at the consensus splice-site at intron 4. 4/5 splice prediction tools predict that this variant eliminates the 5' splicing donor site. This variant is absent in 120402 control chromosomes from ExAC. This variant has been reported as a germline variant in one 20-year-old patient with a metaplastic carcinoma and an invasive ductal carcinoma. The patient also carried BRCA1 exon 3 deletion (Bell_2014). Both variants can be pathogenic and explain the early onset age of this patient. The variant of interest was also found in multiple tumor samples (colorectal carcinoma, esophageal adenocarcinoma and head and neck squamous cell carcinoma), including two confirmed somatic occurrences (Georgieva_2008, Soubeyran_2011, Agrawal_2012 and Seiwert_2015). Taken together, this variant is currently classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692558	SCV000820386	pathogenic	Li-Fraumeni syndrome	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 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 early-onset breast cancer and/or Li-Fraumeni syndrome (PMID: 7887414, 24916180, 28681140; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 439316). 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.
Genome-Nilou Lab	RCV002289694	SCV002582401	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289693	SCV002583063	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000505908	SCV000925734	not provided	not provided		no assertion provided	in vitro