Submissions for variant NM_000546.6(TP53):c.559+1G>A

dbSNP: rs1131691042

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492159	SCV000581171	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	The c.559+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the TP53 gene. This alteration has been reported in a woman diagnosed at age 46 with breast cancer and synchronous pleomorphic leiomyosarcoma (Mannan AU et al. J. Hum. Genet., 2016 Jun;61:515-22). It was also identified in an Indian breast/ovarian cancer cohort (Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196) and in a woman with two breast cancers before age 30 (Wang PY et al. N Engl J Med, 2013 Mar;368:1027-32). In addition, this variant has been reported as a germline alteration and as a somatic alteration in various tumors by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). 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 and will result in the creation or strengthening of a novel splice donor site; however, however direct evidence is insufficient at this time (Ambry internal data). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763418	SCV000894155	pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000786834	SCV001247048	pathogenic	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001210960	SCV001382477	pathogenic	Li-Fraumeni syndrome	2022-12-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 428908). Disruption of this splice site has been observed in individuals with Li-Fraumeni syndrome, breast cancer, and acute lymphoblastic leukemia (PMID: 23484829, 23894400, 26911350, 27619989, 30212483). This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV000786834	SCV002005066	pathogenic	not provided	2021-01-19	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Identified in individuals with breast cancer, one of whom also had a personal history of leiomyosarcoma (Mannan et al., 2016; Li et al., 2018); This variant is associated with the following publications: (PMID: 26911350, 29470806, 30720243, 30212483, 27619989)
Genome-Nilou Lab	RCV000492159	SCV002582378	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289678	SCV002583039	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476180	SCV004204286	likely pathogenic	Adrenocortical carcinoma, hereditary	2021-11-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002289678	SCV004930469	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	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.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786834	SCV000925728	not provided	not provided		no assertion provided	in vitro