Submissions for variant NM_000546.6(TP53):c.18A>C (p.Ser6=)

gnomAD frequency: 0.00002  dbSNP: rs573130482

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213043	SCV000211771	benign	not specified	2014-09-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000161041	SCV000214591	likely benign	Hereditary cancer-predisposing syndrome	2014-10-20	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	RCV001079935	SCV000253307	likely benign	Li-Fraumeni syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000161041	SCV000686724	likely benign	Hereditary cancer-predisposing syndrome	2017-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213043	SCV000697434	likely benign	not specified	2020-08-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589460	SCV000888662	likely benign	not provided	2022-09-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000161041	SCV002582323	likely benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288695	SCV002582985	likely benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001079935	SCV004823869	likely benign	Li-Fraumeni syndrome	2023-09-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000213043	SCV000692103	likely benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357147	SCV001552516	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Ser6= variant was not identified in the literature nor was it identified in the COGR, LOVD 3.0, UMD-LSDB, or UMD TP53 Mutation, databases. The variant was identified in dbSNP (ID: rs573130482) as "With Uncertain significance, other allele", ClinVar (classified as benign by GeneDx; as likely benign by Ambry Genetics, Invitae and three other submitters; as uncertain significance by one submitter), and in IARC TP53 Database. The variant was identified in control databases in 3 of 245504 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European in 3 of 111324 chromosomes (freq: 0.00003), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, Other, and South Asian populations. The p.Ser6= 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. 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.