Heterozygous pathogenic germline variants were identified in TP53 in 1990 as a cause of Li-Fraumeni syndrome (LFS) . LFS was originally labelled SBLA syndrome to reflect the predominance of Sarcoma, Breast/Brain, Leukaemia/Lung cancer and Adrenal carcinoma in the original families [2, 3]. LFS is typically characterized by familial aggregations of very early-onset malignancies covering many tumour sites. These include the characteristic core LFS tumours: soft-tissue sarcomas (STS), osteosarcomas (OS), adrenocortical carcinomas (ACC), central nervous system (CNS) tumours and very early-onset female breast cancers, typically occurring ≤ 30 years. Germline testing for variants in TP53 has been most frequently employed in individuals with core LFS malignancies who fulfil clinical criteria such as classical LFS or “Chompret criteria” (Table 1a/b) [4, 5]. Nevertheless testing for individual tumours without a family history has been carried out in childhood malignancy [6,7,8] or among adult females with extremely early-onset breast cancers with germline TP53 mutations being identified in apparently isolated cases [5, 9]. Such findings have led to the idea being posited that a heritable TP53-related cancer (hTP53rc) syndrome would be a better term than LFS [10, 11]. Very recently two Europe based guidelines for surveillance in hTP53rc syndrome that include intensive surveillance with annual whole body MRI (WBMRI), brain MRI, breast MRI in women from age 20 years and blood testing (for ACC hormones) have been published [12, 13], to add to an American guideline . The guidelines are based around the so-called ‘Toronto’ protocol that has been associated with a reported survival advantage . The introduction of these intensive surveillance programmes, together with the increased availability of cancer predisposition gene testing, means it is particularly timely to understand both accurate variant interpretation and the clinical features where a genuinely pathogenic germline TP53 mutation is likely to be present.
Likelihood of identifying a germline TP53 variant in breast cancer patients
A review suggested that between 3.8–7.7% of women with breast carcinoma aged ≤ 30 harboured pathogenic TP53 variants . However, lower rates have since been reported at 2.2% in 370 Dutch women . Nevertheless these data have shown that a family history of cancer is not a pre-requisite when considering genetic testing of TP53. As early reports showed that the likelihood of germline TP53 reduced sharply after 30 years  and that germline TP53 only very rarely caused familial breast cancer unexplained by BRCA1 or BRCA2 , testing outside this extremely early onset group was rarely undertaken until recently unless the woman with breast cancer’s personal or family history fulfilled at least Chompret/modified Chompret criteria . Nonetheless, very low rates of germline TP53 mutation detected in breast cancer > 30 years has recently been confirmed from the BRIDGES study of 60,466 cases and 53,461 controls . In this study 4/346 had truncating TP53 variants < 30 years compared to 2/53,461 controls (OR = 309) compared to only 3/60,120 (OR = 1.33) > 30 years (Easton D-personal communication).
The development of multi-gene cancer panels has resulted in much more widespread testing of TP53, as it is included in many commercial gene panels offered for germline cancer gene testing in breast cancer, the most frequent indication for commercial panel testing. For instance Ambry genetics provide an online tool  that can be interrogated. From this 79,368 women with breast cancer have been tested and the prevalence of pathogenic TP53 variants was 0.3% (https://www.ambrygen.com/providers/resources/prevalence-tool, accessed 29th August 2020). Aged ≤ 30 years this was 2.5% in 2033 cases compared to 0.18% in 42197 > 46 years. We do not know, however, whether there was pre-testing of those with LFS criteria to reduce the rates in those ≤ 30 or whether some at > 46 had elements of Chompret criteria. Testing in Manchester has found of 381 female breast cancers ≤ 30, TP53 was found in 22 (5.80%), whereas of 921 women > 46 only 2 (0.22%) had TP53 with one having clear LFS criteria reducing those > 46 to only 0.11% without LFS criteria (P < 0.0001). The frequency in women aged 31–46 was still only 0.33% (n = 27623) using the Ambry tool.
Breast cancer gene panel testing and the need for a refined approach
The inclusion of cancer predisposition genes with a wide and variably penetrant phenotype when disrupted, on breast cancer gene panels, is a recognised challenge. Thus many commercial gene panels for breast cancer hereditary predisposition include, in addition to TP53, the CDH1 tumour suppressor gene. Whilst germline CDH1 mutations have been described in 0.34% of lobular breast cancer cases , they are more commonly associated with diffuse gastric cancer, a diagnosis with a dismal prognosis and prophylactic gastrectomy being the main preventable measure. In view of the uncertainties around true penetrance in breast cancer and the real potential for psychological harm, CDH1 is not included in NHS England hereditary breast cancer panel testing, as was determined by the UK Cancer Genetics Group .
Similarly, is it therefore worthwhile including TP53 in gene panels for women at older ages? The potential benefits of the new surveillance protocols in early detection of future cancers and decision making to potentially avoid second cancers from radiotherapy  are clear, as well as the importance of reproductive decision making and offering testing to other potentially at risk family members. However, there are some potential serious harms that can be caused to women who do not have a definite pathogenic variant and potential psychological harm to the tiny proportion that do. Therefore a personalised and refined approach to diagnostic TP53 testing is needed, so that where a variant is detected, it is interpreted accurately and appropriate management put in place as required, with minimal distress.
Interpreting TP53 variants
There are two main concerns when interpreting variants discovered during germline TP53 testing in people with cancer
Is the variant detected the cause of the underlying cancer?
What is the allele frequency of the variant and is it confined to lymphocyte DNA?
Pathogenicity of variants
TP53 is not common for dominantly inherited cancer predisposing genes in that the majority of pathogenic variants are missense . Therefore, complex analyses are required, unless there is already definitive evidence that the variant is pathogenic. Most pathogenic TP53 missense variants reside in the important DNA core binding domain equating to exons 4–8 where the original cases were found . Most pathogenic missense variants act in a dominant negative fashion with protein products forming tetramers with wild type p53 . Information that can help classify variants can be obtained from sources such as the IARC database (https://p53.iarc.fr/) and for general population frequency estimates from the Genome Aggregation Database (gnomAD; https://gnomad.broadinstitute.org/). It is critically important that missense variants should be classified by the widely used ACMG/AMP guidelines . A subcommittee of which, has developed further guidance specific to TP53 . The stringent clinical criteria are in place so that (together with strict functional criteria) missense variants from mass gene panel testing don’t get over-called. These include:
Phenotype information (scores are given for fulfilling Classical LFS or the Chompret criteria, but not for single tumours outwith the criteria);
Importantly at least two different functional tests that predict pathogenicity are required to score in that category . The new ACMG/AMP criteria for germline TP53 variants classification are deliberately stringent to avoid mis-classification . The importance of this has been demonstrated by the potential for ‘over-classification’ of TP53 variants resulting in as high as a frequency as 1 in 500 in gnomAD . If a more stringent approach is used, this provides a more likely 1 in 5000 frequency [30,31,32]. The less parsimonious approaches to classification have resulted in colorectal cancer risk being almost certainly overestimated in LFS ; one report mis-classified five of the six germline reported variants as pathogenic [12, 33]. Given that over age 46 potentially only 0.1–0.2% of women with breast cancer will have a pathogenic variant, there is an almost similar chance that some laboratories will over classify variants that are unlikely to be associated with high or even moderate cancer risk [30, 31].
TP53 allele frequency
Most molecular reports on germline testing from commercial laboratories did not include the allele frequency of the variant until recently (many still do not!). Providing these has become straightforward since moving from Sanger to Next Generation sequencing (NGS) where identification of low DNA allele frequencies has been substantially enhanced. This has been shown to be very valuable in identifying underlying mosaic variants in monogenic conditions such as NF2 . However, there is a particular pitfall in TP53 testing as well as for a number of other genes such as PPM1D and several oncogenes. A frequent cause of low level allele frequencies detected is clonal haematopoiesis of indeterminate potential (CHIP) [35,36,37,38,39]. CHIP has recently become apparent in lymphocyte DNA panel testing by NGS. Older smokers or those who have had chemotherapy or radiotherapy treatments are particularly likely to manifest this. CHIP was first reported in patients over 70 years of age, but can be detected from 30 years of age. The frequency of CHIP increases with age, smoking and chemotherapy or radiotherapy treatments [35,36,37,38,39]. Even with an allele frequency consistent with a germline variant of 50%, clonal haematopoiesis is still possible and should be considered where a TP53 variant is found in a context not usually associated with germline TP53 [36, 39]. The concern is that probably > 50% of TP53 variants found on panel testing are due to CHIP and therefore for those aged over 46 this is likely to be the predominant reason for identifying an apparently pathogenic TP53 variant at all. The presence of true mosaic TP53 alterations should be considered in patients with sporadic cancers strongly suggestive of a pathogenic TP53 variant, such as paediatric ACC, choroid plexus carcinoma, and breast cancer ≤ 30 years, and patients with multiple TP53 core primary tumours . However, the detection of a TP53 variants at significantly < 50% allele frequency on lymphocyte DNA NGS should prompt confirmation of the variant in the tumour and preferably another tissue without lymphocytes such as hair follicle or skin biopsy with fibroblast culture [12, 39]. Where the variant is absent from the tumour (best tested on section without clear infiltration with lymphocytes/macrophages) and other tissues, clonal haematopoiesis is by far the most likely cause (Fig. 1). Even in those with an apparent 50% allele frequency who do not meet LFS criteria, other tissues should be tested because, as many as 6/16 (37.5%) tested in one study who were apparently heterozygote had no evidence of the variant in fibroblast culture .
Breast cancer risks and overall penetrance
That there is a very high risk of breast cancer aged ≤ 30 years is clear from the high detection rates of TP53 pathogenic variants in women with breast cancer at this age. The BRIDGES study showed a 300 fold relative risk potentially equivalent to a 30% risk by the 31st birthday using a 0.1% risk by age 30 for the population in the UK . Even using a 2% detection frequency from the lowest detection rate studies, this would equate to a 100-fold relative risk and a 10% cumulative risk ; the 5% rate [5, 9] would therefore equate to a 25% risk similar to that estimated from cohorts . What is also clear is that this relative risk drops off fairly dramatically after 30 years of age with detection rates in commercial testing of 0.71% for TP53 in 4344 samples aged 31–36, and 0.24% in over 20,000 samples aged 37–46 (https://www.ambrygen.com/providers/resources/prevalence-tool, accessed 28/08/2020, ). Whilst, this might still represent relative risks of 10-fold for that latter period this is now less than would be expected for BRCA1. No reliable cumulative risks are available from large-scale prospective studies and cohort studies that include retrospectively ascertained cases probably exaggerate the lifetime penetrance estimated at around 90% in one study . After age 45 it is not impossible that risks are little different to population risks; in Manchester we have seen no prospective breast cancers in women over 34 years of age with 6/9 occurring aged ≤ 30. Indeed in 15 female TP53 carriers with 83 years of follow up post pathogenic variant report aged > 45 years no breast cancers have been observed.
There is clearly also a very high rate of contralateral breast cancer approaching 4–7% per annum which was significantly higher than for BRCA1 or BRCA2 in those diagnosed aged < 35 . This remained true in prospective analysis and should justify a discussion of risk reducing contralateral mastectomy as long as survival chances are good from the first primary.
The overall cumulative all cancer incidence of germline pathogenic variants in TP53 from familial cases has been estimated at 73–100% by age 70, with risks close to 100% in women [41, 43,44,45]. It is highly likely nonetheless that penetrance is variable. This may be explained in some part by the dominant-negative effects of most pathogenic missense variants. These TP53 dominant-negative missense variants are usually found in families with childhood malignancies and are generally highly penetrant [5, 46]. In contrast, typical loss of function variants (frameshift or nonsense variants, splicing variants, large genomic rearrangements, and non-dominant-negative missense variants), are predominantly identified in families with mainly adult onset cancers and are likely to have a lower overall cancer penetrance [5, 12, 44]. A particularly important example of such a low penetrance, but still pathogenic variant, is the non-dominant-negative missense p.Arg337His variant, present in 0.3% of the Southern Brazilian population [45,46,47,48,49]. Nevertheless this variant is definitely associated with breast cancer risk [48, 49], but its overall penetrance for breast cancer is still to be determined.
Risks from standard breast cancer therapies in TP53 carriers
There is a very high likelihood of subsequent primary tumours in patients with pathogenic TP53 variants [5, 44]. This appears to occur in > 40% of TP53 carriers despite often poor survival from the first primary [5, 44]. Radiotherapy particularly, but also some types of chemotherapy, appear to increase this metachronous primary cancer risk with a particular risk within the radiation field [5, 12, 50]. Studies of chemotherapy/radiotherapy effects on lymphocytes with wild-type or mutant TP53 and on TP53 mouse models appears to provide additional evidence for this risk . Therefore, for women with a significant likelihood of a germline TP53 related breast cancer, testing for pathogenic variants should ideally be performed prior to commencing treatment . If a pathogenic TP53 variant is found particularly in young women with good survival chances mastectomy should be undertaken rather than breast conserving surgery and radiotherapy as per recent guidance . In these young women with high contralateral risk the option of bilateral mastectomy should also be discussed [12, 42].
Effects of germline TP53 pathogenic variant on psychological distress
There is not a great deal published on the impact of TP53 testing on psychological factors. However, there are overall higher levels of distress in families with TP53 pathogenic variants even in those testing negative . More research is needed in this area particularly on the impact of an unexpected TP53 test result from panel testing as in our experience identifying a TP53 variant is often associated with high levels of anxiety.
Breast cancer testing criteria for TP53
Women with breast cancer > 46 years of age have a very low likelihood of a germline pathogenic variant in the absence of Chompret criteria . As described above, this is probably only around 0.1%. These women are probably more likely to have a CHIP diagnosis which will require fibroblast culture and/or obtaining tissue block material. They are also at least as likely to have a variant of uncertain significance that might be considered as ‘hot’ . This does not even take into account the many variants that would still be considered class 3 . The recent guidance recommends that breast cancer patients > 46years at diagnosis should NOT be tested for TP53 . Given the above this seems a sensible approach as the dis-benefits of testing and potential huge anxieties around whether there is variant misclassification, CHIP or the waiting game around a ‘hot’ class 3 that probably will never be classified as high risk are considerably higher than a meaningful result. There are clear recommendations for testing aged ≤ 30 and with Chompret criteria , but this leaves many women with breast cancers aged 31–46 with no clear guidance where testing might be considered (Table 2) albeit still with a low likelihood of detection (~0.33%). National testing panels for breast cancer in the UK now only include BRCA1, BRCA2 and PALB2 and given the above it would seem appropriate to have breast panels for older women with breast cancer that also exclude TP53.
American College of Medical Genetics and Genomics
Association for Molecular Pathology
Central nervous system
European reference network
Gadolinium based contrast agents
Heath care professional
Heritable TP53-related cancer
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DGE and ERW are supported by the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).
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DGE has received travel grants from AstraZeneca.
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Evans, D.G., Woodward, E.R. New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer. Familial Cancer (2020). https://doi.org/10.1007/s10689-020-00207-z
- Breast cancer
- Heritable TP53-related cancer
- Li-fraumeni syndrome