CancerCheck+

Hereditary cancer genetic testing

5%–10% of all cancer cases are hereditary cancer syndromes. Hereditary cancer is suspected when several family members on the same side of the family suffer from the same or similar types of cancer, show signs of the disease at a young age, or have several cancers.

Several inherited cancer syndromes are pretty standard, such as hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, familial adenomatous polyposis, Von-Hippel Lindau syndrome, and multiple endocrine neoplasia type 1 and type 2. Most of these syndromes are autosomal dominant and have high penetrance.

Test Methodology

The Hereditary Cancer Panel is designed to detect single nucleotide variants (SNVs) and small insertions and deletions in 65 genes associated with neurological risk. Targeted regions for this panel include the coding exons and 10 bp intronic sequencesimmediate to the exon-intron boundary of each coding exon in each of these genes. Extracted patient DNA is prepared using targetedhybrid capture, assignment of a unique index, and sequencing via Illumina sequencing by synthesis (SBS) technology. Data is alignedusing human genome build GRCh37. Variant interpretation is performed according to current American College of Medical Geneticsand Genomics (ACMG) professional guidelines for the interpretation of germline sequence variants using Fabric EnterpriseTM Pipeline6.6.15. Variant interpretation and reporting is performed by Fabric Clinical (CLIA ID: 45D2281059 and CAP ID: 9619501). The followingquality filters are applied to all variants: quality <500, allelic balance <0.3, coverage <10x.

Genes Evaluated

APC, ATM, BRCA1, BRCA2, CDH1, CDKN2A, EPCAM, FANCC, FH, HNF1A, HRAS, KIT, MAX, MEN1, MLH1, MSH2, MSH6, MUTYH, NF1, NF2, NSD1, PALB2, PHOX2B, PMS2, PTEN, RET, RUNX1, SDHA, SDHB, SDHC, SDHD, SMAD4, STK11, TMEM127, TP53, TSC1, TSC2, VHL, WT1, BARD1, BRIP1, CHEK2, MBD4, MHS3, NTHL1, POLD1, RAD51D, BMPR1A, CTNNA1, GREM1, POLE, AXIN2, BAP1, CDK4, DICER1, PDGFRA, SMARCA4, RAD51C, TERT, COL1A1, BLM, FBN1, MITF, NBN

Test Limitations

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. At this time, the assay does not detect large deletions and duplications. This analysis also cannot detect pathogenic variants within regions which 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 specified disease pathology whose clinical association has not yet been definitively established. The test may therefore not detect all variants associated with specified disease 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 other interfering substances and matrix-dependent influences. PCR inhibitors, extraneous DNA, and nucleic acid degrading enzymes may adversely affect assay results.

Regulatory Disclosures

This laboratory developed test (LDT) was developed and its performance characteristics were determined by PreCheck HealthServices, Inc. This test was performed at PreCheck Health Services, Inc. (CLIA ID: 10D2210020 and CAP ID: 9101993) that is certifiedunder the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high complexity testing. This assayhas not been cleared or approved by the U.S. Food and Drug Administration (FDA). Clearance or approval by the FDA is not requiredfor the clinical use of this analytically and clinically validated laboratory developed test. This assay has been developed for clinicalpurposes and it should not be regarded as investigational or for research.

References

Lomax ME, Barnes DM, Hupp TR, Picksley SM, et al. Oncogene. 1998, Aug 06. Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members. (PMID: 9704930)

Davison TS, Yin P, Nie E, Kay C, et al. Oncogene. 1998, Aug 06. Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome. (PMID: 9704931)

Chompret A, Brugières L, Ronsin M, Gardes M, et al. British journal of cancer. 2000, Jun. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. (PMID: 10864200)

Al-Tassan N, Chmiel NH, Maynard J, Fleming N, et al. Nature genetics. 2002, Feb. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. (PMID: 11818965)

Sieber OM, Lipton L, Crabtree M, Heinimann K, et al. The New England journal of medicine. 2003, Feb 27. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. (PMID: 12606733)

Kato S, Han SY, Liu W, Otsuka K, et al. Proceedings of the National Academy of Sciences of the United States of America. 2003, Jul 08. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. (PMID: 12826609)

Figueiredo BC, Sandrini R, Zambetti GP, Pereira RM, et al. Journal of medical genetics. 2006, Jan. Penetrance of adrenocortical tumors associated with the germline TP53 R337H mutation. (PMID: 16033918)

Butterworth AS, Higgins JP, Pharoah P. European journal of cancer (Oxford, England : 1990). 2006, Jan. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. (PMID: 16338133)

Achatz MI, Olivier M, Le Calvez F, Martel-Planche G, et al. Cancer letters. 2007, Jan 08. The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. (PMID: 16494995)

Nielsen M, Hes FJ, Nagengast FM, Weiss MM, et al. Clinical genetics. 2007, May. Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. (PMID: 17489848)

Ali M, Kim H, Cleary S, Cupples C, et al. Gastroenterology. 2008, Aug. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. (PMID: 18534194)

Assumpção JG, Seidinger AL, Mastellaro MJ, Ribeiro RC, et al. BMC cancer. 2008, Dec 01. Association of the germline TP53 R337H mutation with breast cancer in southern Brazil. (PMID: 19046423)

Jones N, Vogt S, Nielsen M, Christian D, et al. Gastroenterology. 2009, Aug. Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. (PMID: 19394335)

Molatore S, Russo MT, D'Agostino VG, Barone F, et al. Human mutation. 2010, Feb. MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay. (PMID: 19953527)

Jordan JJ, Inga A, Conway K, Edmiston S, et al. Molecular cancer research : MCR. 2010, May. Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. (PMID: 20407015)

Theodoratou E, Campbell H, Tenesa A, Houlston R, et al. British journal of cancer. 2010, Dec 07. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. (PMID: 21063410)

Win AK, Cleary SP, Dowty JG, Baron JA, et al. International journal of cancer. 2011, Nov 01. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. (PMID: 21171015)

Seidinger AL, Mastellaro MJ, Paschoal Fortes F, Godoy Assumpção J, et al. Cancer. 2011, May 15. Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil. (PMID: 21192060)

Gomes MC, Kotsopoulos J, de Almeida GL, Costa MM, et al. Hereditary cancer in clinical practice. 2012, Mar 28. The R337H mutation in TP53 and breast cancer in Brazil. (PMID: 22455664)

Custódio G, Parise GA, Kiesel Filho N, Komechen H, et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013, Jul 10. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. (PMID: 23733769)

Hahn EC, Bittar CM, Vianna FSL, Netto CBO, et al. PloS one. 2018. TP53 p.Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients. (PMID: 30596752)

Volc SM, Ramos CRN, Galvão HCR, Felicio PS, et al. PloS one. 2020. The Brazilian TP53 mutation (R337H) and sarcomas. (PMID: 31978118)

^{All NGS panels have a turnaround time of 10-14 days for results.}

^{Each panel is designed to detect single nucleotide variants (SNVs) and small insertions and deletions with gene specific limitations.Targeted regions include the coding exons and 10 bp intronic sequences immediate to the exon-intron boundary of each coding exonin each of these genes.}