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August 31, 2021

ACMG secondary findings updated list for reporting of secondary findings, for medically actionable genes in clinical exome and genome sequencing

ACMG secondary findings updated list for reporting of secondary findings, for medically actionable genes in clinical exome and genome sequencing. 

The American College of Medical Genetics and Genomics (ACMG) recently published updated guidance for reporting secondary findings in the context of clinical exome and genome Analyses1. This updated list now consists of 73 genes for which the ACMG recommends reviewing and reporting of known and expected pathogenic variants. Genes in this list were evaluated for medical actionability of the associated condition. 

The Variantyx clinical team continually reviews the ACMG guidelines and recommendations, and updates our secondary findings gene list according to the latest versions available. Hence, patients undergoing testing by either our Genomic Unity® Whole Genome Analysis, Genomic Unity® Exome Plus Analysis or Genomic Unity® Exome Analysis have the choice to opt-in to two additional sets of findings:

  1. Findings in the genes recommended by the American College of Medical Genetics and Genomics (ACMG)
  2. Findings in other genes associated with some degree of clinical actionability (see more information on this option here).

In this post we’ll review some of the genes that were added to the ACMG list of genes and their associated actionability that could impact medical management and decision making.

Under cardiovascular indications, the TTN gene was added, due to its association with dilated cardiomyopathy. New information from large population studies showed significant risk of cardiomyopathy for patients with truncating variants; therefore, the ACMG guidelines now recommend reporting of these variants as secondary findings. Clinical intervention based on the identification of TTN variants was found to be beneficial to both patients and their families.

The Secondary Findings Maintenance Working Group also considered adding genes that are related to inborn errors of metabolism, with the following rules: (1) the existence of a juvenile or later-onset form of the disorder and that early or presymptomatic diagnosis of late-onset disease is unlikely for disorders recently added to the Recommended Uniform Screening Panel (RUSP), (2) that the late-onset form should be highly medically actionable, and (3) that there appear to be a significant number of undiagnosed cases in the population(1)

Genes that were added to this category are BTD, which has a high actionability score of treatment with lifelong oral biotin, and GAA (Pompe disease), that was found to have a later-onset, more mild form of the disorder, and has an FDA-approved effective enzyme replacement therapy. 

Another very interesting gene that was included in this list is RPE65, which is related to early and adult onset of retinal degeneration. The associated symptoms, such as nystagmus, can start shortly after birth, and progress into decrease in their visual field and deterioration of color vision and central visual acuity, until vision impairment or complete loss. RPE65 has an FDA-approved gene replacement therapy that depends on viable retinal cells, and therefore, it may be recommended to administer this therapy earlier rather than later in the disease course.

Cancer related

APCFamilial adenomatous polyposis
RETFamilial medullary thyroid cancer
BRCA1, BRCA2, PALB2Hereditary breast and/or ovarian cancer
SDHD, SDHAF2, SDHC, SDHB, MAX, TMEM127Hereditary paraganglioma–pheochromocytoma syndrome
BMPR1A, SMAD4Juvenile polyposis syndrome
TP53Li–Fraumeni syndrome
MLH1, MSH2, MSH6, PMS2Lynch syndrome
MEN1Multiple endocrine neoplasia type 1
MUTYH*MUTYH-associated polyposis
NF2Neurofibromatosis type 2
STK11Peutz–Jeghers syndrome
PTENPTEN hamartoma tumor syndrome
TSC1, TSC2Tuberous sclerosis complex
VHLvon Hippel–Lindau syndrome
WT1WT1-related Wilms tumor

Cardiac and/or blood vessel related

 FBN1, TGFBR1, TGFBR2,SMAD3, ACTA2 , MYH11 Aortopathies
PKP2, DSP, DSC2, TMEM43, DSG2Arrhythmogenic right ventricular cardiomyopathy
RYR2, CASQ2, TRDNCatecholaminergic polymorphic ventricular tachycardia
TNNT2, LMNA, FLNC, TTNDilated cardiomyopathy
COL3A1Ehlers–Danlos syndrome, vascular type
LDLR, APOB, PCSK9Familial hypercholesterolemia
MYH7, MYBPC3, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2Hypertrophic cardiomyopathyh
KCNQ1, KCNH2Long QT syndrome types 1 and 2
SCN5ALong QT syndrome 3; Brugada syndrome

Genes related to inborn errors of metabolism phenotypes

BTD*Biotinidase deficiency
GLAFabry disease
OTCOrnithine transcarbamylase deficiency
GAA*Pompe disease


HFE**Hereditary hemochromatosis
ACVRL1, ENGHereditary hemorrhagic telangiectasia
RYR1, CACNA1SMalignant hyperthermia
HNF1AMaturity-onset diabetes of the young
RPE65*RPE65-related retinopathy
ATP7B*Wilson disease

*Will be reported only if two likely pathogenic and/or pathogenic variants are identified (homozygous or compound heterozygous state). 
**HFE p.Cys282Tyr homozygous only