ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.559+1G>A (rs1131691042)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492159 SCV000581171 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-10 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) 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. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native 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. As such, this alteration is classified as likely pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763418 SCV000894155 pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; 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 Praxis fuer Humangenetik Tuebingen RCV000786834 SCV001247048 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Invitae RCV001210960 SCV001382477 pathogenic Li-Fraumeni syndrome 2020-05-03 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 and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals with suspected Li-Fraumeni syndrome, breast cancer, and acute lymphoblastic leukemia (PMID: 26911350, 23894400, 23484829, 30212483, 27619989). ClinVar contains an entry for this variant (Variation ID: 428908). Donor and acceptor splice site variants 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.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000786834 SCV000925728 not provided not provided no assertion provided in vitro

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