TP53 NM_000546.6:c.461G>A, Gly154Asp

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.

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.

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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 (Ambry 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.

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 acute myeloid leukemia and/or triple negative breast cancer (PMID: 27276561, 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.