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

gnomAD frequency: 0.00001  dbSNP: rs762846821

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000231149	SCV001949908	uncertain significance	Li-Fraumeni syndrome	2025-02-06	reviewed by expert panel	curation	The NM_000546.6:c.461G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 154 (p.Gly154Asp). This variant received a total of 0.5 points in 1 proband. (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 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; Internal data contributor). This variant has an allele frequency of 0.000001859 (3/1614164 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.2733; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, PM2_supporting, BS3_Supporting, PP3_moderate. (Bayesian Points: 1; VCEP specifications version 2.2; 2/6/2025).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231149	SCV000285197	uncertain significance	Li-Fraumeni syndrome	2025-01-23	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 missense change has been observed in individual(s) with triple negative breast cancer (PMID: 33120919). ClinVar contains an entry for this variant (Variation ID: 237950). Invitae Evidence Modeling incorporating data from in vitro 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238759	SCV005886638	uncertain significance	not specified	2025-02-04	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.461G>A (p.Gly154Asp) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.461G>A has been reported in the literature in an individual with a personal and family history of breast cancer (Zanti_2020). This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Publications report experimental evidence evaluating an impact on protein function, showing either partially reduced function or no deleterious effect (e.g. Kato_2003, Giacomelli_2018, Kotler_2018). The following publications have been ascertained in the context of this evaluation (PMID: 33120919, 12826609, 30224644, 29979965). ClinVar contains an entry for this variant (Variation ID: 237950), including an evaluation from a ClinGen expert panel which classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332150	SCV004040612	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research