ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.461G>A (p.Gly154Asp) (rs762846821)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231149 SCV000285197 uncertain significance Li-Fraumeni syndrome 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 154 of the TP53 protein (p.Gly154Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs762846821, ExAC 0.002%). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 237950). Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 12826609, 30224644 and 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 RCV000492535 SCV000581127 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-06 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 a few similar properties. This alteration has been reported as a somatic mutation 10 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). Yeast based functional studies have shown a partial decrease in transactivation capacity compared to wild type (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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). A similar alteration at this codon, p.G154V (c.461G>T), has been reported in an individual with a history of an astrocytoma and a glioblastoma, and LOH of this alteration was noted in the glioblastoma (Chen P et al. Cancer Genet Cytogenet. 1995 Jul 15;82(2):106-15). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively, yet is predicted to be benign by AGVGD and CADD prediction algorithms (Mathe E, Nucleic Acids Res. 2006 ; 34(5):1317-25, Kircher M, Nat. Genet. 2014 Mar; 46(3):310-5). Since supporting evidence for this variant is conflicting at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000492535 SCV000686740 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-08 criteria provided, single submitter clinical testing
Counsyl RCV000662397 SCV000784812 uncertain significance Li-Fraumeni syndrome 1 2017-01-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764147 SCV000895132 uncertain significance Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 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)

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