Correspondence on ACMG STATEMENT: ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG) by Miller et al

TL;DR

This paper critically examines the ACMG SF v3.0 guidelines for reporting secondary findings in clinical sequencing, highlighting concerns about the interpretation of gene penetrance and the implications for patient management.

Contribution

The authors provide a critical perspective on the ACMG SF v3.0 list, emphasizing uncertainties in gene penetrance and the need for more evidence on clinical benefits and harms.

Findings

Concerns about incomplete penetrance in cardiomyopathy genes

Highlighting the need for better evidence on screening benefits

Emphasizing surveillance over definitive diagnosis

Abstract

We were interested to read the recent update on recommendations for reporting of secondary findings in clinical sequencing1, and the accompanying updated list of genes in which secondary findings should be sought (ACMG SF v3.0)2. Though the authors discuss challenges around incomplete penetrance in considerable detail, we are concerned that the recommendations do not fully convey the degree of uncertainty regarding the penetrance of variants in genes associated with inherited cardiomyopathies, which make up almost a quarter of the list. Since penetrance is incomplete and age-related, individuals found to carry variants will often require surveillance, rather than a one-off definitive diagnostic assessment. There is a lack of evidence regarding benefits, harms, and healthcare costs associated with opportunistic screening.