Submissions for variant NM_000546.6(TP53):c.376-1G>A

gnomAD frequency: 0.00001  dbSNP: rs868137297

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570638	SCV000665059	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-20	criteria provided, single submitter	clinical testing	The c.376-1G>A intronic pathogenic variant results from a G to A substitution one nucleotide upstream from coding exon 4 of the TP53 gene. This alteration (referred to as IVS376-1G>A) has been reported in the germline of a 3 year old male diagnosed with anaplastic rhabdomyosarcoma (Hettmer S et al. Cancer. 2014 Apr; 120(7):1068-75). It has also been reported in an individual with a personal history of rhabdomyosarcoma at age 3, and an early glial lesion at age 11 (Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800144	SCV000939844	pathogenic	Li-Fraumeni syndrome	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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 individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 21305319, 24382691, 27501770, 29752822, 32930885; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 481003). 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.
GeneDx	RCV000786836	SCV001786270	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Observed in two children with brain tumors, one of whom also had a rhabdomyosarcoma, as well as an individual with breast cancer and a child with an adrenocortical tumor who was mosaic for the variant (Hettmer et al., 2014; Villani et al., 2016; Li et al., 2019; Pinto et al., 2021; Wang et al., 2021); Canonical splice site variant expected to result in aberrant splicing; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32930885, 31775759, 24382691, 11857392, 10567903, 26622941, 27489289, 30720243, 29752822, 30913944, 27501770, 35886069, 34926253, 35459788, 24700732, 27146902, 36142413, 35308232, 35791423, 20522432, 35454937, 21305319, 34675114, 33600011)
Genome-Nilou Lab	RCV000570638	SCV002582608	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289803	SCV002583170	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000786836	SCV004026692	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289803	SCV004933395	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-13	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000786836	SCV005625969	pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	The TP53 c.376-1G>A variant disrupts a canonical splice-acceptor site and interferes with normal TP53 mRNA splicing. This variant has been reported in the published literature in individuals/families affected with breast cancer (PMIDs: 29752822 (2018), 35017683 (2022), 35886069 (2022)), rhabdomyosarcoma (PMID: 24382691 (2014)), an early glial lesion (PMID: 27501770 (2016)), and medulloblastoma (PMID: 32930885 (2021)). The frequency of this variant in the general population, 0.0000066 (1/152120 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785531	SCV000924103	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786836	SCV000925730	not provided	not provided		no assertion provided	in vitro
Institute of Medical Sciences, Banaras Hindu University	RCV001255670	SCV001432235	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research