The genetic architecture of inherited cancer risk shapes susceptibility to tumor development, influences age of onset, and determines the spectrum of cancers observed within families. Germline cancer testing provides clinicians with a precise understanding of the molecular mechanisms driving hereditary cancer syndromes, enabling earlier detection, optimized surveillance, targeted risk-reduction strategies, and informed therapeutic decision-making.
PreCheck Health Services’ Comprehensive Hereditary Cancer Panel (116 genes) represents an advanced targeted exome assay designed to evaluate the genetic determinants of inherited cancer predisposition across solid tumors, hematologic malignancies, and multisystem cancer syndromes. The panel incorporates evidence-based curation from ACMG, ClinGen, OMIM, GeneReviews, and current peer-reviewed literature, enabling the identification of clinically actionable germline variants that directly inform cancer screening protocols, prophylactic interventions, treatment planning, and family risk assessment.
❖ Early-onset cancers, including breast, ovarian, colorectal, pancreatic, prostate, thyroid, and endometrial malignancies
❖ Multiple primary cancers in the same individual
❖ Strong family history of cancer, especially clusters of breast, ovarian, colon, prostate, pancreatic, melanoma, or sarcoma
❖ Known or suspected hereditary cancer syndromes, such as BRCA1/2-associated hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, PTEN hamartoma tumor syndrome, and familial adenomatous polyposis
❖ Individuals with cancer diagnosed at unusually young ages, or with tumors rare for their sex or clinical context
❖ Unaffected individuals with a significant family pedigree who seek personalized cancer screening or risk-reduction guidance
❖ Patients considering targeted therapies (e.g., PARP inhibitors, immunotherapy) where germline status may influence eligibility or treatment response
1.DNA Damage Response and Double-Strand Break Repair
Genes mediating sensing and repair of double-strand breaks and maintaining genomic stability:
❖ ATM, ATR, BRCA1, BRCA2, PALB2, BRIP1, BARD1, CHEK2, BLM, NBN, FAN1, FANCM, RECQL4, WRN
2. Mismatch Repair, Nucleotide Excision Repair, and Replication Fidelity
Genes responsible for correcting base mispairs, replication errors, and bulky DNA adducts:
❖ MLH1, MSH2, MSH6, PMS2, MLH3, MSH3, EPCAM, MUTYH, NTHL1, MBD4, DDB2, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XPC, POLD1, POLE, POLH
3.Telomere Biology, Ribosome Function, and Bone Marrow Failure Syndromes
Genes regulating telomere length, shelterin complex integrity, and ribosomal/hematopoietic stability:
❖ TERC, TERT, TINF2, POT1, DKC1, NHP2, NOP10, WRAP53, SBDS, DIS3L2, SRP72
4.Tumor Suppressor Pathways and Cell-Cycle Regulation
Genes controlling cell-cycle checkpoints, apoptosis, and transcriptional regulation:
❖ TP53, RB1, CDKN2A, CDKN1B, CDKN1C, CDK4, STK11, PTEN, SMAD4, RUNX1, CEBPA, HOXB13, IKZF1, PAX5, REST, CTNNA1, BUB1B, TRIP13
5.RAS/MAPK and PI3K/AKT Signaling Pathways
Genes involved in growth factor signaling, oncogenic kinase activation, and downstream proliferative cascades:
❖ HRAS, NF1, NF2, KIT, PDGFRA, PIK3CA, ALK, MET, RET, PRKAR1A, TMEM127, LZTR1, RHBDF2
6.Wnt, Hedgehog, and Developmental Signaling Pathways
Genes driving embryonic patterning and adult tissue homeostasis, frequently altered in hereditary tumor syndromes:
❖ APC, AXIN2, GREM1, PTCH1, PTCH2, SUFU, BMPR1A, SMAD4, GPC3, MITF
7.Hamartoma, Polyposis, and Gastrointestinal Cancer Syndromes
Genes predisposing to adenomatous, hamartomatous, or mixed polyposis and associated GI malignancies:
❖ APC, MUTYH, SMAD4, BMPR1A, STK11, PTEN, GREM1, EXT1, EXT2, MEN1, CDC73
8.Renal, Endocrine, and Neuroendocrine Tumor Predisposition
Genes associated with hereditary renal cell carcinoma, endocrine neoplasia, pheochromocytoma/paraganglioma, and related syndromes:
❖ FH, FLCN, VHL, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, MEN1, AIP, PHOX2B
9.Hereditary Breast, Ovarian, and Gynecologic Cancer
Genes conferring elevated risk for breast, ovarian, and related cancers:
❖ BRCA1, BRCA2, PALB2, BRIP1, RAD51C, RAD51D, BARD1, CHEK2, ATM, TP53, PTEN, CDH1
10.Other Hereditary Cancer and Tumor Syndromes
Genes associated with additional solid tumor and leukemic predisposition:
❖ BAP1, CYLD, DICER1, ELANE, GATA2, GPC3, HOXB13, RHBDF2, SMARCA4, SMARCB1, SMARCE1, WT1
Genes Analyzed 116 Hereditary Cancer-related genes.
Technology Platform Illumina NGS (Hybrid-Capture Target Enrichment).
Coverage Metrics >98% bases at ≥20× read depth.
Variant Types Detected SNVs and small indels (≤20 bp) within coding exons ±10 bp intronic boundaries.
Reference Genome GRCh38/hg38.
Bioinformatics Pipeline SeqOne™, ACMG/AMP compliant.
Confirmatory Testing Sanger sequencing or orthogonal method as indicated.
Turnaround Time ~10 calendar days.
Quality Metrics Read quality ≥Q30; allelic balance ≥0.3; minimum coverage 20×
1.Hereditary Breast, Ovarian, and Gynecologic Cancer Management
❖ Identify individuals at elevated risk for breast, ovarian, endometrial, and fallopian tube cancers
❖ Guide personalized screening (e.g., annual breast MRI, transvaginal ultrasound, CA-125 monitoring)
❖ Inform decisions on risk-reducing mastectomy or salpingo-oophorectomy
❖ Support targeted therapy choices, including PARP inhibitor eligibility
2.Colorectal, Gastric, and Gastrointestinal Cancer Prevention
❖ Detect Lynch syndrome and polyposis syndromes
❖ Optimize colonoscopy intervals and implement upper GI surveillance when indicated
❖ Identify carriers at risk for duodenal, gastric, pancreatic, or small bowel cancers
3.Endocrine, Renal, and Neuroendocrine Tumor Syndromes
❖ Diagnose hereditary pheochromocytoma/paraganglioma
❖ Identify risk for medullary thyroid carcinoma, pituitary tumors, or hyperparathyroidism
❖ Support early detection pathways that modify morbidity and survival
4.Hematologic and Bone Marrow Failure Predisposition
❖ Detect germline variants linked to leukemia risk
❖ Identify familial bone marrow failure syndromes requiring modified chemotherapy conditioning
❖ Enable early monitoring for cytopenias, MDS evolution, or clonal hematopoiesis
5.Pancreatic, Prostate, and Melanoma Risk Assessment
❖ Detect hereditary risk genes influencing pancreatic cancer surveillance
❖ Guide prostate cancer screening and disease management in BRCA2 and HOXB13 carriers
❖ Identify melanoma risk associated with CDKN2A, MITF, and BAP1
6.Family Counseling and Cascade Testing
❖ Support targeted testing of at-risk relatives for gene-specific cancer risk
❖ Enable personalized prevention plans across multiple generations
❖ Reduce long-term cancer burden through early identification and risk-reduction strategies
7.Comprehensive Cancer Risk Management Across Specialties
❖ Unify germline data with imaging, pathology, and patient history to guide whole-patient care
❖ Inform treatment, surveillance, surgical planning, and long-term preventive strategies
❖ Provide durable, longitudinal risk frameworks aligned with NCCN hereditary cancer guidelines
Risk Stratification and Early Detection Identify individuals with germline pathogenic variants conferring high or moderate cancer risk, enabling tailored screening protocols (e.g., earlier and more frequent breast MRI, colonoscopy, pancreatic surveillance, or dermatologic exams).
Treatment Selection and Therapeutic Optimization Inform systemic therapy choices, including use of PARP inhibitors in BRCA1/2 and other homologous recombination–deficient tumors, immunotherapy considerations in mismatch repair–deficient or POLE-mutated cancers, and targeted agents in specific kinase or pathway-driven syndromes.
Family Risk Assessment and Carrier Evaluation Clarify recurrence risk in families, identify carriers, and support reproductive planning based on confirmed pathogenic variants.
Integrated Longitudinal Cancer Risk Management Support multidisciplinary care teams (oncology, genetics, surgery, primary care, and psychology) in constructing a unified, gene-informed risk management plan that evolves over time as guidelines, evidence, and variant classifications are updated.
Pharmacogenetics Testing (for drug metabolism and gene-drug interactions)
Together, these tools enable precision medicine teams to offer a fully customized, data-driven treatment plan for each patient.
Hereditary cancer testing is now a cornerstone of precision oncology, enabling clinicians to uncover the genetic foundations of inherited cancer risk with far greater clarity than traditional family-history–based assessment alone. With a rigorously curated gene panel, high analytic performance, and clinically validated interpretation, PreCheck Health Services provides providers with the germline insights necessary to guide surveillance, refine therapeutic decisions, inform prophylactic interventions, and support long-term risk management. This comprehensive approach empowers clinicians to deliver earlier, more precise, and more preventive care across the full spectrum of hereditary cancer syndromes.
The Comprehensive Hereditary Cancer Panel is designed to detect single-nucleotide variants (SNVs) and small insertions and deletions in 116 genes associated with cancer risk. Targeted regions for this panel include the coding exons and 10 bp intronic sequences immediately to the exon-intron boundary of each coding exon in each of these genes. Extracted patient DNA is prepared using targeted hybrid capture, assignment of a unique index, and sequencing via Illumina sequencing by synthesis (SBS) technology. Data is aligned using the human genome build GRCh38. Variant interpretation is performed according to current American College of Medical Genetics and Genomics (ACMG) professional guidelines for the interpretation of germline sequence variants using SeqOne Pipeline.
AIP, ALK, ANKRD26, APC, ATM, ATR, AXIN2, BAP1, BARD1, BLM, BMPR1A, BRCA1, BRCA2, BRIP1, BUB1B, CDC73, CDH1, CDK4, CDKN1B, CDKN1C, CDKN2A, CEBPA, CHEK2, CTNNA1, CYLD, DDB2, DICER1, DIS3L2, DKC1, ELANE, EPCAM, ERCC2, ERCC3, ERCC4, ERCC5, EXT1, EXT2, FAN1, FANCM, FH, FLCN, GATA2, GPC3, GREM1, HOXB13, HRAS, IKZF1, KIT, LZTR1, MAX, MBD4, MEN1, MET, MITF, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, NBN, NF1, NF2, NHP2, NOP10, NTHL1, PALB2, PAX5, PDGFRA, PHOX2B, PIK3CA, PMS2, POLD1, POLE, POLH, POT1, PRKAR1A, PRSS1, PTCH1, PTCH2, PTEN, RAD51C, RAD51D, RB1, RECQL4, REST, RET, RHBDF2, RUNX1, SBDS, SDHA, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, SRP72, STK11, SUFU, TERC, TERT, TINF2, TMEM127, TP53, TRIP13, TSC1, TSC2, VHL, WRAP53, WRN, WT1, XPA, XPC
This test aims to detect all clinically relevant variants within the coding regions of the genes evaluated. Pathogenic and likely pathogenic variants detected in these genes should be confirmed by orthogonal methods. Detected genetic variants classified as benign, likely benign, or of uncertain significance are not included in this report. Homopolymer regions and regions outside of the coding regions cannot be captured by the standard NGS target enrichment protocols. Currently, the assay does not detect large deletions and duplications. This analysis also cannot detect pathogenic variants within regions that were not analyzed (e.g., introns, promoter and enhancer regions, long repeat regions, and mitochondrial sequence). This assay is not designed to detect mosaicism and is not designed to detect complex gene rearrangements or genomic aneuploidy events. It is important to understand that there may be variants in these genes undetectable using current technology. Additionally, there may be genes associated with hereditary cancer pathology whose clinical association has not yet been definitively established. The test may therefore not detect all variants associated with hereditary cancer pathology. The interpretation of variants is based on our current understanding of the genes in this panel and is based on current ACMG professional guidelines for the interpretation of germline sequence variants. Interpretations may change over time as more information about the genes in this panel becomes available. Qualified health care providers should be aware that future reclassifications of genetic variants can occur as ACMG guidelines are updated. Factors influencing the quantity and quality of extracted DNA include, but are not limited to, collection technique, the amount of buccal epithelial cells obtained, the patient’s oral hygiene, and the presence of dietary or microbial sources of nucleic acids and nucleases, as well as other interfering substances and matrix-dependent influences. PCR inhibitors, extraneous DNA, and nucleic acid-degrading enzymes may adversely affect assay results.
This laboratory-developed test (LDT) was developed, and its performance characteristics were determined by PreCheck Health Services, Inc. This test was performed at PreCheck Health Services, Inc. (CLIA ID: 10D2210020 and CAP ID: 9101993), which is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high complexity testing.
This assay has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Clearance or approval by the FDA is not required for the clinical use of this analytically and clinically validated laboratory-developed test. This assay has been developed for clinical purposes, and it should not be regarded as investigational or for research.
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