Beside the scope of genetic diagnostics – in rare cases – genetic changes may be found by coincidence, which are not related to the requested analysis. If these variants turn out to be pathogenic or likely pathogenic and there are treatment options or preventive care measures available for you or your family (based on the currently valid guidelines of the American College of Medical Genetics and Genomics; ACMG SF v3.2; Miller et al., 2023, PMID: 37347242) these variants can be reported as a secondary finding.
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General Information
Secondary findings do not involve active investigation of the entire ACMG gene list, but rather are variants that are discovered incidentally as part of the diagnostic process. Reporting of secondary findings is only applicable if the patient consented and is free of charge.
An active investigation of the ACMG gene list is also offered, it can be selected as an additional option for most NGS-based germline investigations. In such cases, the “ACMG genes” (see below) are actively screened for pathogenic or likely pathogenic alterations, and an independent report will be issued, even if no pathogenic or likely pathogenic variants were found.
Notice:
According to German legislation, predictive diagnostics for diseases that do not occur until adulthood may not be performed in minors. For this reason, the analysis of the genes BRCA1, BRCA2, HFE, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, and TTR for minors is omitted.
If, the phenotypic spectrum of these genes is relevant to the clinical indication of the patient, these genes will not be excluded from the analysis.
Sample Report
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 |
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| 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
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