Submissions for variant NM_000546.6(TP53):c.474C>T (p.Arg158=)

gnomAD frequency: 0.00009  dbSNP: rs139200646

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163158	SCV000213675	likely benign	Hereditary cancer-predisposing syndrome	2016-02-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206827	SCV000259803	likely benign	Li-Fraumeni syndrome	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001704160	SCV000523505	likely benign	not provided	2020-08-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26205736, 24729566, 20010306, 29958926, 29979965, 32324779, 28861920)
Color Diagnostics, LLC DBA Color Health	RCV000163158	SCV000686741	likely benign	Hereditary cancer-predisposing syndrome	2016-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000424020	SCV000918327	benign	not specified	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.474C>T results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African control individuals in the gnomAD database is approximately 11.57 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant was also found in 2/9884 individuals who are cancer-free and older than age 70, suggesting this variant is unlikely to be pathogenic. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000424020	SCV002069584	likely benign	not specified	2019-08-09	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225476	SCV002505075	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163158	SCV002530463	benign	Hereditary cancer-predisposing syndrome	2020-11-11	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000163158	SCV002582586	likely benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288716	SCV002582887	likely benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing