Submissions for variant NM_000546.6(TP53):c.460G>A (p.Gly154Ser)

gnomAD frequency: 0.00004  dbSNP: rs137852789

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206813	SCV000259695	uncertain significance	Li-Fraumeni syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 154 of the TP53 protein (p.Gly154Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with breast cancer, kidney cancer and acute lymphoblastic leukemia (PMID: 28664506, 29300620, 31321604; Invitae). ClinVar contains an entry for this variant (Variation ID: 133284). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 20407015, 29979965). 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	RCV000573570	SCV000664404	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	The p.G154S variant (also known as c.460G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 460. The glycine at codon 154 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a patient diagnosed with breast cancer at age 38 and in a patient diagnosed with renal cancer at age 40 (Yang XR et al. Breast Cancer Res.Treat. 2017 Oct;165(3):687-697; Bittar CM et al. Fam Cancer, 2019 10;18:451-456). This variant was also reported in 4/60,466 breast cancer cases and in 3/53,461 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 partial loss of transactivation capacity and predicted to affect several p53 isoforms (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986050	SCV001134869	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573570	SCV001359462	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 154 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 partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 20407015), functional in transcription activation assay in human cells (PMID: 33257846) and in human cell growth assay (PMID: 29979965). A different human cell growth assay was inconclusive regarding the variant impact on protein function (PMID: 30224644). This variant has been reported in three individuals affected with breast cancer (PMID: 28664506, 28861920, 30287823), in one individual affected each with renal cancer who met the Birch criteria for Li-Fraumeni syndrome testing (PMID: 31321604) and pediatric B-cell acute lymphoblastic leukemia (PMID: 29300620). This variant also has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID TP53_010102). This variant has been identified in 6/282632 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.
GeneDx	RCV000986050	SCV002005650	uncertain significance	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer, renal cancer, or hyperdiploid acute lymphocytic leukemia (Yang et al., 2017; Qian et al., 2018; Momozawa et al., 2018; Bittar et al., 2019; Dorling et al., 2021); Published functional studies are inconclusive: partially functional or competent transactivation, and growth suppression abilities comparable to wildtype (Kato et al., 2003; Shiraishi et al., 2004; Jordan et al., 2010; Giacomelli et al., 2018; Kotler et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31321604, 28664506, 29979965, 28861920, 14559903, 20407015, 12826609, 30886117, 35008396, 30840781, 34234460, 33471991, 30287823, 15510160, 30224644, 29300620, 36479692, 37352403, 22768918)
Genome-Nilou Lab	RCV000573570	SCV002582076	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288604	SCV002582639	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477307	SCV002789085	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	2022-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226204	SCV003922733	uncertain significance	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.460G>A (p.Gly154Ser) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) 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 4e-06 in 251252 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.460G>A has been reported in the literature in individuals affected with breast or renal cancer (e.g. Yang_2017, Bittar_2019). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The variant has been reported to be partially-functional based on overall transactivation activity (TA) on several different promoters as measured in yeast assays (Kato_2003, Jordan_2010), with significantly elevated transactivation activities at higher protein expression levels (Jordan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20407015, 28664506, 31321604, 30224644,27463065). ClinVar contains an entry for this variant (Variation ID: 133284). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000986050	SCV004562211	uncertain significance	not provided	2023-10-13	criteria provided, single submitter	clinical testing	The TP53 c.460G>A; p.Gly154Ser variant (rs137852789) is reported in the literature in individuals affected with breast and renal cancer (Bittar 2019, Yang 2017). This variant is also reported in ClinVar (Variation ID: 133284). This variant is found in the non-Finnish European population with an allele frequency of 0.005% (6/129022 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.638). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bittar CM et al. TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling. Fam Cancer. 2019 Oct;18(4):451-456. PMID: 31321604. Yang XR et al. Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia. Breast Cancer Res Treat. 2017 Oct;165(3):687-697. PMID: 28664506.
All of Us Research Program, National Institutes of Health	RCV000206813	SCV004823802	uncertain significance	Li-Fraumeni syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 154 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 partially functional in yeast transactivation assays (IARC database and PMID: 12826609, 20407015), functional in transcription activation assay in human cells (PMID: 33257846) and in human cell growth assay (PMID: 29979965). A different human cell growth assay was inconclusive regarding the variant impact on protein function (PMID: 30224644). This variant has been reported in three individuals affected with breast cancer (PMID: 28664506, 28861920, 30287823), in one individual affected each with renal cancer who met the Birch criteria for Li-Fraumeni syndrome testing (PMID: 31321604) and pediatric B-cell acute lymphoblastic leukemia (PMID: 29300620). This variant also has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID TP53_010102). This variant has been identified in 6/282632 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.
Baylor Genetics	RCV004567035	SCV005054354	uncertain significance	Adrenocortical carcinoma, hereditary	2023-11-15	criteria provided, single submitter	clinical testing
Laboratory of Translational Genomics, National Cancer Institute	RCV000119797	SCV000154269	not provided	Sarcoma		no assertion provided	not provided
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332120	SCV004040539	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003905134	SCV004721537	uncertain significance	TP53-related disorder	2024-01-16	no assertion criteria provided	clinical testing	The TP53 c.460G>A variant is predicted to result in the amino acid substitution p.Gly154Ser. This variant was reported in an individual with breast cancer (Yang et al 2017. PubMed ID: 28664506) or an individual with renal cancer (Bittar CM et al 2019. PubMed ID: 31321604). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Functional studies have been inconclusive regarding the impact of this missense change on TP53 function (Kato S et al 2003. PubMed ID: 12826609; Jordan JJ et al 2010. PubMed ID: 20407015; Kotler E et al 2018. PubMed ID: 29979965). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.