Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

Abstract

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS), an autosomal dominant cancer predisposition disorder associated with high risk of malignancy, including early onset breast cancers, sarcomas, adrenocortical carcinomas and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants has been shown to decrease mortality; therefore, accurate and consistent classification of variants across clinical and research laboratories is crucial to patient care. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were applied to twenty ACMG/AMP criteria while nine were deemed not applicable. The original strength level for ten criteria was also adjusted due to current evidence. Use of the TP53-specific guidelines and sharing of clinical data amongst experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% in comparison with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.

Germline TP53 Testing in Breast Cancers: Why, When and How?

“…Specific ACMG/AMP criteria for germline TP53 variant classification have been defined by a TP53 variant curation expert panel, under the umbrella of ClinGen. These specific criteria indicate that at least two different functional analyses are required to predict pathogenicity [22].…”

New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer

“…It is critically important that missense variants should be classified by the widely used ACMG/AMP guidelines [24]. A subcommittee of which, has developed further guidance specific to TP53 [25]. 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.…”

“…Importantly at least two different functional tests that predict pathogenicity are required to score in that category [25]. The new ACMG/AMP criteria for germline TP53 variants classification are deliberately stringent to avoid mis-classification [25].…”

“…Importantly at least two different functional tests that predict pathogenicity are required to score in that category [25]. The new ACMG/AMP criteria for germline TP53 variants classification are deliberately stringent to avoid mis-classification [25]. 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 [30].…”

“…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 Variant interpretaƟon using specific criteria (25) & classified as per 5 Ɵer system (53) Fig. 1 Flow-chart to aid in distinguishing mosaicism from CHIP and subsequent variant interpretation generally highly penetrant [5,46].…”