Submissions for variant NM_000546.6(TP53):c.1135C>T (p.Arg379Cys)

dbSNP: rs749061599

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166233	SCV000217013	likely benign	Hereditary cancer-predisposing syndrome	2023-05-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559034	SCV000629777	uncertain significance	Li-Fraumeni syndrome	2023-07-17	criteria provided, single submitter	clinical testing	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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 186611). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is present in population databases (rs749061599, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 379 of the TP53 protein (p.Arg379Cys).
Color Diagnostics, LLC DBA Color Health	RCV000166233	SCV000906803	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 379 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies have reported this variant to have partial transactivating activity (IARC yeast assays, PMID: 12826609) and no effects on human cell growth suppression assays (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251414 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.
Genome-Nilou Lab	RCV002288759	SCV002582932	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000166233	SCV002583195	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000559034	SCV004823714	uncertain significance	Li-Fraumeni syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 379 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies have reported this variant to have partial transactivating activity (IARC yeast assays, PMID: 12826609) and no effects on human cell growth suppression assays (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251414 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000166233	SCV005402571	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 GRCh38:17:7669656:G>A was assigned evidence codes ['BS3_Moderate', 'BP4'] and an overall classification of Likely benign