Submissions for variant NM_000546.6(TP53):c.903A>G (p.Pro301=)

gnomAD frequency: 0.00003  dbSNP: rs72661120

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163363	SCV000213900	likely benign	Hereditary cancer-predisposing syndrome	2014-08-28	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.
GeneDx	RCV000760104	SCV000517836	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22311583, 15523690, 9039222, 18330889, 22089350, 24929325, 21878961, 28861920)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000436196	SCV000540571	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.2% (31/16512) South Asian; ClinVar: 1 LB
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081862	SCV000557356	benign	Li-Fraumeni syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163363	SCV000686780	likely benign	Hereditary cancer-predisposing syndrome	2016-10-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163363	SCV000803172	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000760104	SCV000889886	benign	not provided	2023-02-08	criteria provided, single submitter	clinical testing
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV001270284	SCV001450504	likely benign	Familial cancer of breast		criteria provided, single submitter	case-control
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225477	SCV002505064	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163363	SCV002532722	benign	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000163363	SCV002582508	likely benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288718	SCV002582808	likely benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002288718	SCV004015635	benign	Li-Fraumeni syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000436196	SCV004024294	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355179	SCV001549984	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Pro301= variant was identified in 7 of 364 proband chromosomes (frequency: 0.02) from Indian individuals or families with breast cancer and was not identified in 372 control chromosomes from healthy individuals (Damineni 2014). The variant was also identified in dbSNP (ID: rs72661120 as “With Likely benign allele”) and ClinVar (classified as likely benign by Ambry Genetics, GeneDx, LMM, Color Genomics and Institute for Biomarker Research and as benign by Invitae). The variant was not identified in GeneInsight-COGR, LOVD 3.0, or IARC TP53 Database. The variant was identified in control databases in 69 of 246266 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 65 of 30782 chromosomes (freq: 0.002), African in 1 of 15304 chromosomes (freq: 0.00007), Other in 1 of 5486 chromosomes (freq: 0.0002), and European Non-Finnish in 2 of 111720 chromosomes (freq: 0.00002), while it was not observed in the Latino, Ashkenazi Jewish, East Asian or Finnish populations. The p.Pro301= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.