Submissions for variant NM_000546.6(TP53):c.861G>C (p.Glu287Asp)

gnomAD frequency: 0.00001  dbSNP: rs748891343

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481706	SCV000571522	uncertain significance	not provided	2016-08-29	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.861G>C at the cDNA level, p.Glu287Asp (E287D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAC). This variant has been observed as being apparently somatically acquired in tumor specimens (Bartkova 2012, Gatalica 2014) and is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Glu287Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. TP53 Glu287Asp occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the DNA binding domain (Bode 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 Glu287Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568299	SCV000667208	likely benign	Hereditary cancer-predisposing syndrome	2023-04-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000568299	SCV001359328	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 287 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have shown that the mutant protein is functional in yeast transactivation assays (IARC database; PMID: 12826609) and does not exhibit dominiant-negative effect nor loss of function in human cell growth suppression assays (PMID: 30224644). However, in a human cell proliferation assay, the mutant protein was non-functional (PMID: 29979965). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251484 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001214612	SCV001386300	uncertain significance	Li-Fraumeni syndrome	2023-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 287 of the TP53 protein (p.Glu287Asp). This variant is present in population databases (rs748891343, gnomAD 0.007%). 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: 422130). 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. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609). 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.
Sema4, Sema4	RCV000568299	SCV002532715	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-13	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000568299	SCV002581988	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289642	SCV002583110	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV004760528	SCV005373750	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-09	criteria provided, single submitter	curation	According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: BP4 (supporting benign): AlignGVGD class: C0; BayesDel (no AF): -0.117111, BS3 (strong benign): Kato et al: Transactivation assays in yeast show retained function (76-140% activity) or super-transactivation function Giacomelli et al: No evidence of DNE + no evidence of LOF
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000568299	SCV005402575	likely benign	Hereditary cancer-predisposing syndrome	2024-04-12	criteria provided, single submitter	curation	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For TP53, we used the output of the Naïve Bayes classifier that synthesized data from four different TP53 MAVEs in Fayer et al. (2021) (PMID: 34793697). If the classifier predicted a variant to be "Functionally abnormal," the variant was assigned PS3 evidence and no BS3 evidence. If a variant was predicted to be "Functionally normal," BS3_moderate evidence was used with no PS3 evidence. This variant GRCh38:17:7673759:C>G was assigned evidence codes ['BS3_Moderate', 'BP4'] and an overall classification of Likely benign