Submissions for variant NM_000546.6(TP53):c.354A>T (p.Thr118=)

gnomAD frequency: 0.00001  dbSNP: rs751978853

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163547	SCV000214105	likely benign	Hereditary cancer-predisposing syndrome	2015-06-01	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	RCV000225831	SCV000285190	likely benign	Li-Fraumeni syndrome	2025-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000421071	SCV000514936	benign	not specified	2015-07-16	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477594	SCV000602267	benign	not provided	2023-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163547	SCV000911992	likely benign	Hereditary cancer-predisposing syndrome	2017-11-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000421071	SCV000920319	likely benign	not specified	2018-07-02	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.354A>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.7e-05 in 245848 control chromosomes (gnomAD). The observed variant frequency is approximately 1.43 folds higher than the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.354A>T in individuals affected with Li-Fraumeni Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000989724	SCV001140267	likely benign	Squamous cell carcinoma of the head and neck	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163547	SCV002530449	likely benign	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000163547	SCV002582253	likely benign	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288719	SCV002582914	likely benign	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000225831	SCV004823814	likely benign	Li-Fraumeni syndrome	2024-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907509	SCV004723994	likely benign	TP53-related disorder	2019-03-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).