Prevention with ACMG

Module PRV14

Not only physical characteristics and abilities can be inherited, but also the genetic predisposition to certain diseases. By analyzing genetic information, we can help to individualize preventive measures and, if necessary, adapt treatment options. Our ACMG module examines a list of genes compiled by the American College of Medical Genetics and Genomics and is relevant in preventive care. This way, potential health risks can be identified and responded to at an early stage.

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What is ACMG?

ACMG stands for American College of Medical Genetics and Genomics. An interdisciplinary group of experts in this association published a list for identifying and managing risks for selected genetic diseases.1 This list is regularly updated to include new findings from research. For the variants investigated and reported, there are established measures to reduce the risk or mitigate the disease. The focus lies on tumor diseases and cardiovascular diseases. However, the list also includes other genes whose variants can cause, for example, metabolic diseases.

The association of genes with certain disease patterns can also be found here.

Further information about the mentioned disease areas can be found in our modules tumor diseases, cardiovascular diseases, iron and copper storage disorders, hypercholesterolemia, eye diseases, malignant hyperthermia, familial diabetes, and metabolic diseases. In these modules, we have supplemented the genes in the ACMG guidelines for the individual disease areas with additional relevant genes based on our expertise.

Field Report

Alex R., 25 years old

Lifestyle: little exercise, smoker

Result: For Alex R., a variant in the gene LMNA was found that contributes to an increased risk for dilative cardiomyopathy.

Konsequenz: Alex R. now regularly attends check-ups with a cardiologist and has given up smoking. If necessary, measures can be taken at an early stage to mitigate the limitation in cardiac function.

“The test has opened my eyes to my increased risk for heart diseases. I am grateful to know this now and to be able to take countermeasures in time.”

Bei Alex R. wurde eine Variante im Gen LMNA gefunden, die zu einem erhöhten Risiko für dilatative Kardiomyopathien beiträgt.

How Does Genetic Risk Assessment Work?

Many factors contribute to the development of diseases. We help to determine the genetic risk. This allows known genetic variants to be reliably detected.

In the module ACMG, 81 genes are analyzed that are associated with an increased risk for tumor diseases, cardiovascular diseases, metabolic diseases, and others. In case of an increased risk, early detection measures and lifestyle adjustments can be useful. In the event of illness, therapies can be more target-oriented.

ACMG Gene Sets

Genes Related to Cancer Phenotypes

Gene


Phenotype


OMIM ID


Inheritance


Variants to Report


APC Familial adenomatous polyposis 175100 AD All P and LP
RET Familial medullary thyroid cancer 155240 AD All P and LP
Also associated with multiple endocrine neoplasia type 2
BRCA1 Hereditary breast and/or ovarian cancer 604370 AD All P and LP
BRCA2 Hereditary breast and/or ovarian cancer 612555 AD All P and LP
PALB2 Hereditary breast and/or ovarian cancer 114480 AD All P and LP
SDHD Hereditary paraganglioma-pheochromocytomasyndrome 168000 AD All P and LP
SDHAF2 Hereditary paraganglioma-pheochromocytomasyndrome 601650 AD All P and LP
SDHC Hereditary paraganglioma-pheochromocytomasyndrome 605373 AD All P and LP
SDHB Hereditary paraganglioma-pheochromocytomasyndrome 115310 AD All P and LP
MAX Hereditary paraganglioma-pheochromocytomasyndrome 171300 AD All P and LP
TMEM127 Hereditary paraganglioma-pheochromocytomasyndrome 171300 AD All P and LP
 BMPR1A Juvenile polyposis syndrome 174900 AD All P and LP
SMAD4 Juvenile polyposis syndrome All P and LP
Also associated with hereditary hemorrhagic telangiectasia
TP53 Li–Fraumeni syndrome 151623 AD All P and LP
MLH1 Lynch syndrome (HNPCC) 609310 AD All P and LP
MSH2 Lynch syndrome (HNPCC) 120435 AD All P and LP
MSH6 Lynch syndrome (HNPCC) 614350 AD All P and LP
PMS2 Lynch syndrome (HNPCC) 614337 AD All P and LP
MEN1 Multiple endocrine neoplasia type 1 131100 AD All P and LP
MUTYH MUTYH-associated polyposis 608456 AR P and LP (2 variants)
NF2 Neurofibromatosis type 2 101000 AD All P and LP
STK11 Peutz-Jeghers syndrome 175200 AD All P and LP
PTEN PTEN hamartoma tumor syndrome 158350 AD All P and LP
RB1 Retinoblastoma 180200 AD All P and LP
TSC1 Tuberous sclerosis complex 191100 AD All P and LP
TSC2 Tuberous sclerosis complex 613254 AD All P and LP
VHL von Hippel-Lindau syndrome 193300 AD All P and LP
WT1 WT1-related Wilms tumor 194070 AD All P and LP

AD = autosomal dominant; AR = autosomal recessive; LP = likely pathogenic; P = pathogenic

Genes Related to Cardiovascular Phenotypes

Gene


Phenotype


OMIM ID


Inheritance


Variants to Report


FBN1 Aortopathies 154700 AD All P and LP
TGFBR1 Aortopathies 609192 AD All P and LP
TGFBR2 Aortopathies 610168 AD All P and LP
SMAD3 Aortopathies 613795 AD All P and LP
ACTA2 Aortopathies 611788 AD All P and LP
MYH11 Aortopathies 132900 AD All P and LP
PKP2 Arrhythmogenic right ventricularcardiomyopathy
(A subcategory of ACM)
609040 AD All P and LP
DSP Arrhythmogenic right ventricularcardiomyopathy
(A subcategory of ACM)
607450 AD All P and LP
Also associated with dilated cardiomyopathy (DCM) as a primary disease
DSC2 Arrhythmogenic right ventricularcardiomyopathy
(A subcategory of ACM)
610476 AD All P and LP
TMEM43 Arrhythmogenic right ventricularcardiomyopathy
(A subcategory of ACM)
604400 AD All P and LP
DSG2 Arrhythmogenic right ventricularcardiomyopathy
(A subcategory of ACM)
610193 AD All P and LP
RYR2 Catecholaminergic polymorphic ventriculartachycardia 604772 AD All P and LP
CASQ2 Catecholaminergic polymorphic ventriculartachycardia 611938 AR P and LP (2 variants)
TRDN Catecholaminergic polymorphic ventriculartachycardia 615441 AR P and LP (2 variants)
Also associated with long QT syndrome
TNNT2 Dilated cardiomyopathy 601494 AD All P and LP
Also associated with hypertrophic cardiomyopathy (HCM)
LMNA Dilated cardiomyopathy 115200 AD All P and LP
Also associated with a skeletal myopathy (ie, myofibrillar myopathy)
FLNC Dilated cardiomyopathy 617047 AD All P and LP
Also associated with a skeletal myopathy (ie, myofibrillar myopathy)
TTN Dilated cardiomyopathy 604145 AD All P and LP
Only loss-of-function variants should be reported as a secondary finding
BAG3* Dilated cardiomyopathy 613881 AD All P and LP
Also associated with a skeletal myopathy (ie, myofibrillar myopathy)
DES* Dilated cardiomyopathy 604765 AD All P and LP
Also associated with a skeletal myopathy (ie, myofibrillar myopathy)
RBM20* Dilated cardiomyopathy 613172 AD All P and LP
TNNC1* Dilated cardiomyopathy 611879 AD All P and LP
COL3A1 Ehlers-Danlos syndrome,vascular type 130050 AD All P and LP
LDLR Familial hypercholesterolemia 143890 SD All P and LP
APOB Familial hypercholesterolemia 144010 AD All P and LP
PCSK9 Familial hypercholesterolemia 603776 AD All P and LP
MYH7 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
192600 AD All P and LP
Also associated with dilated cardiomyopathy (DCM) as a primary disease
MYBPC3 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
115197 AD All P and LP
TNNI3 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
613690 AD All P and LP
TPM1 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
115196 AD All P and LP
MYL3 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
608751 AD All P and LP
ACTC1 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
612098 AD All P and LP
PRKAG2 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
600858 AD All P and LP
Pathogenic variants in this gene are associated with a metabolic storage disease that mimics HCM, but also can involve skeletal muscle.
MYL2 Hypertrophic cardiomyopathy
(Individuals with primary HCM may present in late stage disease with a DCM phenotype)
608758 AD All P and LP
KCNQ1 Long QT syndrome types 1 and 2 192500 AD All P and LP
KCNH2 Long QT syndrome types 1 and 3 613688 AD All P and LP
SCN5A Long QT syndrome 3, Brugada syndrome 603830,601144 AD All P and LP
Also associated with dilated cardiomyopathy (DCM) as a primary disease.
CALM1 Long QT syndrome type 14 616247 AD All P and LP
CALM2 Long QT syndrome type 15 616249 AD All P and LP
CALM3 Long QT syndrome type 16 618782 AD All P and LP

AD = autosomal dominant; AR = autosomal recessive; SD = semidominant; LP = likely pathogenic; P = pathogenic

*New Genes according to ACMG SF v3.2; Miller et al., 2023, PMID: 37347242

Genes Related to Inborn Errors of Metabolism Phenotypes

Gene


Phenotype


OMIM ID


Inheritance


Variants to Report


BTD Biotinidase deficiency 253260 AR P and LP (2 variants)
GLA Fabry disease 301500 XL All hemi-, het-, homozygous P and LP
Gene also applies to the cardiovascular category
OTC Ornithine transcarbamylase deficiency 311250 XL All hemi-, het-, homozygous P and LP
GAA Pompe disease 232300 AR P and LP (2 variants)

AR = autosomal recessive; XL = X-linked; LP = likely pathogenic; P = pathogenic

Genes Related to Miscellaneous Phenotypes

Gene


Phenotype


OMIM ID


Inheritance


Variants to Report


HFE Hereditary hemochromatosis 235200 AR p.C282Y homozygotes only
Transcript for the HFE gene is NM_000410.3
ACVRL1 Hereditary hemorrhagic telangiectasia 600376 AD All P and LP
ENG Hereditary hemorrhagic telangiectasia 187300 AD All P and LP
RYR1 Malignant hyperthermia 145600 AD All P and LP
CACNA1S Malignant hyperthermia 601887 AD All P and LP
HNF1A Maturity-onset of diabetes of the young 600496 AD All P and LP
RPE65 RPE65-related retinopathy 204100,613794 AR P and LP (2 variants)
ATP7B Wilson disease 277900 AR P and LP (2 variants)
TTR* Hereditary TTR amyloidosis 105210 AD All P and LP

AD = autosomal dominant; AR = autosomal recessive; LP = likely pathogenic; P = pathogenic

*New Genes according to ACMG SF v3.2; Miller et al., 2023, PMID: 37347242

Gene Set

Actionable Core Gene Set According to ACMG (3.2)
(PRV14, 81 Genes)

ACTA2, ACTC1, ACVRL1, APC, APOB, ATP7B, BAG3, BMPR1A, BRCA1, BRCA2, BTD, CACNA1S, CALM1, CALM2, CALM3, CASQ2, COL3A1, DES, DSC2, DSG2, DSP, ENG, FBN1, FLNC, GAA, GLA, HFE, HNF1A, KCNH2, KCNQ1, LDLR, LMNA, MAX, MEN1, MLH1, MSH2, MSH6, MUTYH, MYBPC3, MYH11, MYH7, MYL2, MYL3, NF2, OTC, PALB2, PCSK9, PKP2, PMS2, PRKAG2, PTEN, RB1, RBM20, RET, RPE65, RYR1, RYR2, SCN5A, SDHAF2, SDHB, SDHC, SDHD, SMAD3, SMAD4, STK11, TGFBR1, TGFBR2, TMEM127, TMEM43, TNNC1, TNNI3, TNNT2, TP53, TPM1, TRDN, TSC1, TSC2, TTN, TTR, VHL, WT1

You Are also Welcome to Take a Look at the Following Areas

Hypercholesterolemia

Elevated blood lipid values can favor heart attacks

Cardiovascular Diseases

Vascular diseases can develop gradually, and heart diseases are often discovered too late

Contact Us

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Diagnostic Support

We will assist you in selecting the diagnostic strategy – whether as a person seeking advice or as a physician.

PRV team of CeGaT

References

1 Miller, D. T. et al. ACMG SF v3.2 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). Genetics in medicine : official journal of the American College of Medical Genetics 25, 100866; 10.1016/j.pediatrneurol.2021.03.005 (2023).