Submissions for variant NM_000546.6(TP53):c.168A>G (p.Glu56=)

gnomAD frequency: 0.00003  dbSNP: rs574255227

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563399	SCV000664382	likely benign	Hereditary cancer-predisposing syndrome	2015-06-08	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.
Color Diagnostics, LLC DBA Color Health	RCV000563399	SCV000908802	likely benign	Hereditary cancer-predisposing syndrome	2017-11-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000198234	SCV001469317	likely benign	not provided	2020-08-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001438960	SCV001641841	likely benign	Li-Fraumeni syndrome	2024-12-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000563399	SCV002582288	likely benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288803	SCV002582950	likely benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001438960	SCV004823842	likely benign	Li-Fraumeni syndrome	2023-02-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000198234	SCV001551585	likely benign	not provided		no assertion criteria provided	clinical testing	The TP53 p.Glu56= variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs574255227) as "With Likely benign allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics), Cosmic (1x found in Haematopoietic and lymphoid tissue), and in IARC TP53 Database (1x). The variant was not identified in COGR, or LOVD 3.0 databases. The variant was identified in control databases in 10 of 246224 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 10 of 30780 chromosomes (freq: 0.0003), but not in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Glu56= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The functional and co-segregation analysis of p.Glu56= transactivation in the germline, using a Dual-Luciferase Assay in TP53-null H1299, SAOS-2 and TP53 wild-type SK-N-AS cells, resulted in similar promoter activity levels to that of the WT TP53 plasmid. Authors concluded that it is likely that the p.Glu56= variant belongs to a class of rare single nucleotide polymorphisms (Said 2016). 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.