Submissions for variant NM_000546.6(TP53):c.461G>A (p.Gly154Asp)

gnomAD frequency: 0.00001  dbSNP: rs762846821

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000662397	SCV001949908	uncertain significance	Li-Fraumeni syndrome 1	2021-08-26	reviewed by expert panel	curation	This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3_Moderate). However, transactivation assays show partially functional variant 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_Supporting; PMID: 12826609, 30224644). This variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting; PMID: internal expert panel member contributor). In summary, the clinical significance of TP53 c.461G>A; p.Gly154Asp is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS2_supporting, BS3_Supporting, PP3_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231149	SCV000285197	uncertain significance	Li-Fraumeni syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 154 of the TP53 protein (p.Gly154Asp). This variant is present in population databases (rs762846821, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 237950). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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.
Ambry Genetics	RCV000492535	SCV000581127	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	The p.G154D variant (also known as c.461G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 461. The glycine at codon 154 is replaced by aspartic acid, an amino acid with similar properties. This variant has been reported in a cohort of triple negative breast cancer patients from Cyprus (Zanti M et al. Cancers (Basel), 2020 Oct;12:). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is not anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). In addition, this alteration did not segregate with disease in one family tested in our laboratory (internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000492535	SCV000686740	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 154 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant functional in transactivation and cell growth and proliferation assays (PMID: 12826609, 329979965, 0224644). This variant has been reported in an individuals affected with triple negative breast cancer s in the literature (PMID: 33120919). This variant has been identified in 2/251272 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.
Counsyl	RCV000662397	SCV000784812	uncertain significance	Li-Fraumeni syndrome 1	2017-01-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478839	SCV000895132	uncertain significance	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001558177	SCV001780069	uncertain significance	not provided	2020-09-28	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 has a deleterious effect on protein structure/function; Observed in individuals with leukemia, but germline vs. somatic status was not clarified (Dutta 2020); This variant is associated with the following publications: (PMID: 30309854, 32164171, 28861920, 29979965, 22678923, 19005564, 27891503, 27146902, 15221790, 15138567, 30840781)
Myriad Genetics, Inc.	RCV000662397	SCV004017872	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.
Baylor Genetics	RCV003469152	SCV004206231	uncertain significance	Adrenocortical carcinoma, hereditary	2023-09-14	criteria provided, single submitter	clinical testing
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332150	SCV004040612	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research