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

Abstract

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.

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

“… a Two missense variants that were included in the assumed benign reference set by Fortuno et al, (p.Glu339Lys and p.Gly360Ala) have now been excluded since they are now present as germline variants in the latest release of the IARC TP53 Database (R19, August 2018)…”

“…After proving that there was no linear correlation among the three components of the model ( R 2 AlignGVGD vs. BayesDel =0.16, R 2 SGR vs. Align‐GVGD =0.0003, R 2 SGR vs. BayesDel =3E‐05), these components were combined to provide an assessment of pathogenicity that incorporates the independent data relating to changes in amino acid physicochemical properties, evolutionary conservation, and previous counts of germline and somatic events – where the combined LR is the product of the individual LRs. LRs from bioinformatic tools were available for all possible 2,314 missense variants (original outputs can be found in Table S4 of Fortuno et al, ), while LRs from SGR were available for 1,121 single nucleotide substitutions (1,007 unique missense variants) with enough germline/somatic counts. A posterior probability of pathogenicity could therefore be calculated for 1,121 missense variants.…”

“…Individuals heterozygous for a TP53 germline pathogenic variant (hereafter termed carriers) have been previously estimated to have a cumulative cancer incidence of 50% by age 31 and almost 100% by age 70 (Mai et al, ). More recently, ascertainment of pathogenic variant carriers through less stringent criteria has resulted in the traditional estimates of penetrance being revised downwards for many breast cancer predisposition genes, including TP53 (de Andrade et al, ; Fortuno, James, & Spurdle, ), and extension of the spectrum of cancers linked to the classic LFS phenotype (Rana et al, ). The identification of germline TP53 variants is increasing due to the expanded use of genomic technologies generally in individuals affected by cancer, creating challenges for variant classification and clinical decision‐making.…”

Whole-body MRI within a surveillance program for carriers with clinically actionable germline TP53 variants - the Swedish constitutional TP53 study SWEP53

“…One of the aims of SWEP53 is to delineate the cancer risks and potential modifying factors in the two phenotypic groups of germline TP53 carriers, namely the LFS phenotype and the hereditary breast cancer phenotype. A meta-analysis [12] found the prevalence of germline TP53 mutations to be 7.7% in women with breast cancer < 30 years old without a LFS family history, and a 7% prevalence of TP53 mutations amongst women < 31 years old with a HER2-positive breast cancer. Thus, TP53 correlated breast cancer is more likely to be HER2 positive.…”

“…Fifteen percent of all children will develop cancer before the age of 15 years [11]. In recent years, pathogenic germline TP53 variants have also been found to cause hereditary breast cancer without childhood cancers or classic LFS [12]. The reasons behind these differences in phenotypes are today unknown, and there are no obvious differences in the genetic variants found between these two groups of patients.…”