Improved, ACMG-compliant, in silico prediction of pathogenicity for missense substitutions encoded by <i>TP53</i>
 variants

Fortuño, Cristina; James, Paul; Young, Erin L.; Feng, Bing; Olivier, Magalí; Pesaran, Tina; Tavtigian, Sean V.; Spurdle, Amanda B.

doi:10.1002/humu.23553

Cited by 34 publications

(32 citation statements)

References 20 publications

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“…(Spurdle et al, 2008;Spurdle et al, 2012;Thompson et al, 2014), and here we have developed the first quantitative model for TP53 variant classification. We estimated probability of pathogenicity using two bioinformatic tools previously selected as the best-performing tools for TP53 (Fortuno, James, Young, et al, 2018), but in this analysis, we converted the binary outputs to a continuous range of LRs for improved discrimination between variants. In addition, we used the relationship between somatic and germline counts (SGR), assisted by (Bouaoun et al, 2016), as a measure of the effect of genetic variation on TP53 gene function.…”

Section: Discussionmentioning

confidence: 99%

“…Align‐GVGD (http://agvgd.hci.utah.edu) is a gene‐specific tool that considers physicochemical properties of amino acids and evolutionary conservation. The Grantham variation (GV) and deviation (GD) scores were calculated for each variant as previously described (Mathe et al, ), using an optimized protein multi‐sequence alignment (Fortuno, James, Young, et al, ). Overall, 76% of the assumed benign variants and 11% of assumed pathogenic variants fell into the lowest A‐GVGD category (C0), while 59% of assumed pathogenic variants and none of the assumed benign variants fell in the highest category (C65; Mathe et al, ; Tavtigian et al, ).…”

Section: Methodsmentioning

confidence: 99%

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A quantitative model to predict pathogenicity of missense variants in the TP53 gene

et al. 2019

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Germline pathogenic variants in the TP53 gene cause Li‐Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high‐intensity screening programs. The aim of this study was to develop an evidence‐based quantitative model that integrates independent in silico data (Align‐GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. To do this, a likelihood ratio for pathogenicity (LR) was derived from each component calibrated using reference sets of assumed pathogenic and benign missense variants. A posterior probability of pathogenicity was generated by combining LRs, and algorithm outputs were validated using different approaches. A total of 730 TP53 missense variants could be assigned to a clinically interpretable class. The outputs of the model correlated well with existing clinical information, functional data, and ClinVar classifications. In conclusion, these quantitative outputs provide the basis for individualized assessment of cancer risk useful for clinical interpretation. In addition, we propose the value of the novel SGR approach for use within the ACMG/AMP guidelines for variant classification.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A quantitative model to predict pathogenicity of missense variants in the TP53 gene

et al. 2019

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“…In silico analysis with IARC database including BaynesDel, PolyPhen2, REVEL and SIFT showed that 27 of these mutations might impair p53 transactivation activity. Mutations of arginine residue at codons R175H, R248Q, R273H and R282W might lead to gain of function enhancing oncogenesis and drug resistance (Table S2). Other genes co‐mutated with TP53 included BCOR (19%), RUNX1 (16%), NOTCH1 (16%), NRAS (11%), ASXL1 (11%) and BCORL1 (11%).…”

Section: Resultsmentioning

confidence: 99%

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Leung

Zhang

et al. 2019

American J Hematol

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The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.

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“…To do this, we excluded variants originally reported in the published studies as (likely) pathogenic if they were consistently reported in ClinVar as “(Likely) Benign”. In addition, variants found in ClinVar with conflicting classifications between “(Likely) Benign”/“Uncertain” were excluded if additional computational (Fortuno et al., ) and functional (Kato et al., ) evidence supported this exclusion. We also included in the meta‐analyses variants reported as uncertain by the original publications if they were consistently reported in ClinVar as “(Likely) Pathogenic”, or in ClinVar with conflicting classifications between “(Likely) Pathogenic”/“Uncertain” and if additional computational and functional evidence supported this inclusion.…”

Section: Methodsmentioning

confidence: 99%

Current review ofTP53pathogenic germline variants in breast cancer patients outside Li-Fraumeni syndrome

2018

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Pathogenic germline variants in TP53 predispose carriers to the multi‐cancer Li‐Fraumeni syndrome (LFS). Widespread multigene panel testing is identifying TP53 pathogenic variants in breast cancer patients outside the strict clinical criteria recommended for LFS testing. We aimed to assess frequency and clinical implications of TP53 pathogenic variants in breast cancer cohorts ascertained outside LFS. Classification of TP53 germline variants reported in 59 breast cancer studies, and publicly available population control sets was reviewed and identified evidence for misclassification of variants. TP53 pathogenic variant frequency was determined for: breast cancer studies grouped by ascertainment characteristics; breast cancer cohorts undergoing panel testing; and population controls. Early age of breast cancer onset, regardless of family history or BRCA1/BRCA2 previous testing, had the highest pick‐up rate for TP53 carriers. Patients at risk of hereditary breast cancer unselected for features of LFS carried TP53 pathogenic variants at a frequency comparable to that of other non‐BRCA1/2 breast cancer predisposing genes, and ∼threefold more than reported in population controls. These results have implications for the implementation of TP53 testing in broader clinical settings, and suggest urgent need to investigate cancer risks associated with TP53 pathogenic variants in individuals outside the LFS spectrum.

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Improved, ACMG-compliant, in silico prediction of pathogenicity for missense substitutions encoded by TP53 variants

Cited by 34 publications

References 20 publications

A quantitative model to predict pathogenicity of missense variants in the TP53 gene

A quantitative model to predict pathogenicity of missense variants in the TP53 gene

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Current review ofTP53pathogenic germline variants in breast cancer patients outside Li-Fraumeni syndrome

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