Submissions for variant NM_000546.6(TP53):c.877G>T (p.Gly293Trp)

gnomAD frequency: 0.00001  dbSNP: rs587780076

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000462367	SCV001429620	likely benign	Li-Fraumeni syndrome	2020-08-11	reviewed by expert panel	curation	Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.877G>T (p.Gly293Trp) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: BS3; BS2_Supporting.
GeneDx	RCV000213062	SCV000149650	uncertain significance	not provided	2020-06-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: retained transactivation activity (Kato 2003, Monti 2011); Observed in individuals with sarcoma, glioblastoma, neurofibromatosis, and/or breast cancer (Chung 1991, Mitchell 2013, Tung 2016); This variant is associated with the following publications: (PMID: 17606709, 26976419, 22045683, 15924253, 30352134, 1686725, 24729566, 25801821, 23894400, 26367797, 26659599, 12826609, 8829653, 26933808, 21343334, 30840781)
Ambry Genetics	RCV000115741	SCV000187101	likely benign	Hereditary cancer-predisposing syndrome	2021-03-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Counsyl	RCV000410614	SCV000488448	uncertain significance	Li-Fraumeni syndrome 1	2016-04-07	criteria provided, single submitter	clinical testing
Invitae	RCV000462367	SCV000545297	uncertain significance	Li-Fraumeni syndrome	2022-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 293 of the TP53 protein (p.Gly293Trp). This variant is present in population databases (rs587780076, gnomAD 0.002%). This missense change has been observed in individual(s) with glioblastoma and neurofibromatosis, sarcoma, and breast cancer (PMID: 1686725, 23894400, 26976419). ClinVar contains an entry for this variant (Variation ID: 127826). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 17606709, 21343334, 30224644, 30840781). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000115741	SCV000691660	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with tryptophan at codon 293 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 the mutant protein to be functional in yeast transcription activation assays (IARC database and PMID: 12826609, 17606709, 21343334) and in human cell growth suppression assays (PMID: 30224644). This variant has been reported in a 17 year-old affected with glioblastoma and diagnosed with neurofibromatosis type 1 (PMID: 1686725), individuals affected with adult-onset sarcoma (PMID: 23894400), and individuals affected with breast cancer (PMID: 26976419, 33471991). This variant has been identified in 3/282876 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.
Myriad Genetics, Inc.	RCV000410614	SCV004017850	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.