Submissions for variant NM_000546.6(TP53):c.639A>G (p.Arg213=)

gnomAD frequency: 0.01275  dbSNP: rs1800372

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000036533	SCV000111073	benign	not specified	2015-03-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162403	SCV000212733	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: 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203086	SCV000257782	benign	Li-Fraumeni syndrome 1	2015-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV000206135	SCV000262407	benign	Li-Fraumeni syndrome	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000036533	SCV000305116	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000203086	SCV000407069	benign	Li-Fraumeni syndrome 1	2018-01-12	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.
Counsyl	RCV000203086	SCV000488466	benign	Li-Fraumeni syndrome 1	2016-04-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162403	SCV000537359	benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001572845	SCV000605419	benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001572845	SCV001830120	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31748977, 30796655, 27957778, 29979965, 25896519)
Genetics Program, Instituto Nacional de Cancer	RCV002307374	SCV002515180	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000036533	SCV002551036	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000162403	SCV002582425	benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000203086	SCV002583086	benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000203086	SCV004015627	benign	Li-Fraumeni syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000203086	SCV004017896	benign	Li-Fraumeni syndrome 1	2023-04-12	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036533	SCV000060188	benign	not specified	2008-09-15	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000036533	SCV000692079	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000203086	SCV000733709	benign	Li-Fraumeni syndrome 1		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162403	SCV000788225	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357034	SCV001552359	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Arg213= variant was identified in 13 of 844 proband chromosomes (frequency: 0.02) from individuals or families with breast, ovarian, gastric or non-small cell lung cancer (Arcand 2015, Juvan 2007 17436385, Palacio-Rua 2014, Deben 2017). The variant was identified in dbSNP (rs1800372) as “with other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics, Color and 8 other submitters; and as likely benign by Illumina and True Health Diagnostics) and LOVD 3.0 (observed 9x). The variant was identified in control databases in 3407 of 277,174 chromosomes (33 homozygous) at a frequency of 0.01, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 67 of 24,030 chromosomes (freq: 0.003), Other in 126 of 6466 chromosomes (freq: 0.02), Latino in 455 of 34,418 chromosomes (freq: 0.01), European in 2209 of 126,676 chromosomes (freq: 0.02), Ashkenazi Jewish in 343 of 10,152 chromosomes (freq: 0.03), East Asian in 2 of 18,866 chromosomes (freq: 0.0001), Finnish in 119 of 25,784 chromosomes (freq: 0.005), and South Asian in 86 of 30,782 chromosomes (freq: 0.003). The p.Arg213= variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs at a non-conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001572845	SCV001797847	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000036533	SCV001809091	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000036533	SCV001905939	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036533	SCV001928843	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001572845	SCV001969071	likely benign	not provided		no assertion criteria provided	clinical testing