UK recommendations forSDHAgermline genetic testing and surveillance in clinical practice

Abstract

SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice.

Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report

“…In contrast to SDHB which is a highly penetrant tumor predisposition gene, SDHA confers a much lower penetrance and severity, estimates of which are largely unknown ( 18 , 19 ). Present surveillance guidelines for SDHx-associated PGL/PCC recommend plasma metanephrines, whole body and dedicated neck MRI, and complete blood count starting from age 6-8 years ( 19 ). Our patient represents the first case of a metastatic PNET in the setting of germline heterozygous pathogenic variants in the VHL and SDHA genes.…”

Principles of molecular testing for hereditary cancer

“…13 Clinical practice guidelines and recommendations exist for the management of Lynch syndrome, 33,37,103,236,237 as well as polyposis syndromes. neurofibromatosis type 1, 243,244 Li-Fraumeni syndrome, 245 von Hippel-Lindau disease, 246 multiple endocrine neoplasia type 1, 247 basal cell carcinomas in Gorlin syndrome, 248 pheochromocytoma and paraganglioma, 249,250 SDHA pathogenic germline variant carriers, 109 and DICER1 tumor predisposition. 57 However, for many rare hereditary cancer syndromes or genes, evidence-based guidelines for patient management and surveillance are not presently available.…”

“…Eligibility for genetic testing varies across jurisdictions and according to which hereditary cancer syndrome is suspected, 101,106–109 however, eligibility criteria generally take into account the proband's clinical features (eg, age of cancer diagnosis, cancer type, tumor characteristics), family history (eg, number of first‐ or second‐degree relatives with related cancers), ancestry (eg, Ashkenazi Jewish), or the presence of a known pathogenic/likely pathogenic variant in the family. For some cancer types, universal genetic testing may be recommended.…”

“…For example, multiple professional organizations recommend universal germline genetic testing for all patients with epithelial ovarian cancers 110–113 . When a familial variant is not already known, it is generally most informative to begin with testing a proband who is affected by cancer 107 . Once a pathogenic variant is identified, family members can receive predictive testing for the familial variant.…”

“…Based on the ACMG/AMP criteria, variants are classified to one of five levels: pathogenic (class 5), likely pathogenic (class 4), uncertain significance (class 3), likely benign (class 2), or benign (class 1) 171 . Since the publication of these guidelines in 2015, further specifications have been developed, 173 which relate to the application of specific evidence (eg, loss of function variants, 106 evidence from functional studies 107 ), and for the interpretation of variants in specific genes (eg, CDH1 174 ). The guidelines have also been modeled as a Bayesian classification framework 175 .…”