Submissions for variant NM_000546.6(TP53):c.1015G>C (p.Glu339Gln)

dbSNP: rs17882252

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000697643	SCV001737935	likely benign	Li-Fraumeni syndrome	2024-09-06	reviewed by expert panel	curation	The NM_000546.6: c.1015G>C variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by glutamine at amino acid 339 (p.Glu339Gln). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been observed in 2 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Ambry lab). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, BS3, BP4. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024).
Ambry Genetics	RCV000130594	SCV000185467	likely benign	Hereditary cancer-predisposing syndrome	2021-05-12	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.
GeneDx	RCV000213068	SCV000211766	likely benign	not provided	2023-06-05	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697643	SCV000826267	likely benign	Li-Fraumeni syndrome	2024-08-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130594	SCV000904077	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 339 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant is functional in yeast transactivation assays and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 2/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000697643	SCV004823728	uncertain significance	Li-Fraumeni syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 339 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant is functional in yeast transactivation assays and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 2/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.