Submissions for variant NM_000546.6(TP53):c.97-6C>T

gnomAD frequency: 0.00847  dbSNP: rs35117667

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206386	SCV000261915	benign	Li-Fraumeni syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094499	SCV000407073	benign	Li-Fraumeni syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000579891	SCV000686785	benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000581997	SCV000806251	benign	not specified	2017-03-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001711984	SCV001156538	benign	not provided	2022-03-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001711984	SCV001940125	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000581997	SCV002069201	benign	not specified	2021-03-05	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225507	SCV002505081	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV002225507	SCV002515174	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000581997	SCV002551125	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000579891	SCV002582430	benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001094499	SCV002583092	benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579891	SCV002693947	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Fulgent Genetics, Fulgent Genetics	RCV002503814	SCV002813099	likely benign	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-04-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150095	SCV003837777	benign	Breast and/or ovarian cancer	2021-10-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001094499	SCV004015631	benign	Li-Fraumeni syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000581997	SCV000692098	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000579891	SCV000788227	likely benign	Hereditary cancer-predisposing syndrome	2017-09-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356670	SCV001551905	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 c.97-6C>T variant was identified in 1 of 210 proband chromosomes (frequency: 0.00476) from individuals or families with hereditary breast and ovarian cancer (Yorczyk 2015). The variant was also identified in dbSNP (ID: rs35117667) as “With other allele”, ClinVar (as benign by Invitae and likely benign by Illumina), Clinvitae (as benign), LOVD 3.0 (as unknown), and IARC TP53 Database. The variant was not identified in Cosmic, UMD TP52 Mutation Database, or Database of germline p53 mutations. The variant was identified in control databases in 719 of 276982 chromosomes (9 homozygous) at a frequency of 0.002596 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 657 (9 homozygous) of 23962 chromosomes (freq: 0.02742), Other in 3 of 6460 chromosomes (freq: 0.000464), Latino in 51 of 34398 chromosomes (freq: 0.001483), European (Non-Finnish) in 8 of 126616 chromosomes (freq: 0.000063), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The c.97-6C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.