Submissions for variant NM_000546.6(TP53):c.1101-1G>A

dbSNP: rs876658982

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222547	SCV000274903	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-08-21	criteria provided, single submitter	clinical testing	The c.1101-1G>A intronic variant results from a G to A one nucleotide upstream from coding exon 10 of the TP53 gene. This alteration was identified in an individual with a personal history of breast cancer and sarcoma (Prejac J et al. World J Surg Oncol, 2021 Aug;19:254). Another alteration at this same splice junction, c.1101-2A>G, was identified in a 2 year old patient with an adrenocortical tumor. RNA analysis from this tumor showed a deletion of the first 10 base pairs of exon 11 (coding exon 10) resulting in a frame shift and a predicted stop codon 82 nucleotides after the wild type termination codon (Pinto EM et al. Fam. Cancer 2011 Mar;10(1):141-6). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. Based on current evidence c.1101-1G>A is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466199	SCV000545300	pathogenic	Li-Fraumeni syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 of the TP53 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. 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: 20967502, 34452612). ClinVar contains an entry for this variant (Variation ID: 231146). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant disrupts the C-terminal region of the TP53 protein important for TP53 regulation and nuclear localization (PMID: 20932800, 26205489). While functional studies have not been performed to directly test the effect of this variant on TP53 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000222547	SCV002582329	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001252683	SCV002582991	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001535521	SCV003929637	likely pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Identified in an individual meeting Chompret criteria with a personal history of breast cancer and sarcoma and family history of early-onset breast cancer (Prejac et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31105275, 2247074, 15510160, 34452612)
Myriad Genetics, Inc.	RCV001252683	SCV004931946	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.
Fulgent Genetics, Fulgent Genetics	RCV005016585	SCV005651975	likely pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Familial pancreatic carcinoma; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2023-12-29	criteria provided, single submitter	clinical testing
Centre for translational and clinical research, University Hospital Centre Zagreb	RCV001252683	SCV001161439	likely pathogenic	Li-Fraumeni syndrome 1		no assertion criteria provided	clinical testing	This sequence change affects an acceptor splice site in the last intron (intron 10) of the TP53 gene. It is expected to disrupt mRNA splicing and likely results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency) and has not been reported in the literature in individuals with a TP53-related disease. Variant 1bp upstream of this variant is described in patient with pediatric adrenocortical tumor (PMID-20967502).
GenomeConnect - Invitae Patient Insights Network	RCV001535521	SCV001749483	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 04-02-2015 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.