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 59 genes associated with hereditary cancer risk. Targeted regions for this panel include the coding exons and 10 bp intronic sequences immediate 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 SBS technology. Data is aligned using human genome build GRCh37. Variant interpretation is performed according to current ACMG professional guidelines for the interpretation of germline sequence variants using Fabric EnterpriseTM Pipeline 6.6.14.

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, HOXB13, PDGFRA, SMARCA4, RAD51C

Test Limitations

This test aims to detect all clinically relevant variants within the coding regions of the genes listed in the method above. Exons 12-15 of PMS2, exons 9-11, 15-27, and 31-35 of NF1, show high homology to pseudogenes and/or contain large repeat regions. Pathogenic and Likely Pathogenic variants in these genes and exons should be confirmed by orthogonal technology. 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, mitochondrial sequence). This assay is not designed to detect mosaicism; possible cases of mosaicism may be investigated at the discretion of the laboratory director. This test is not designed to detect complex gene rearrangements or genomic aneuploidy events. eLab only reports findings within the genes that are included within the panel. 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. These interpretations may change over time as more information about the genes and this individual’s clinical phenotype becomes available. Variants that have been classified as benign, likely benign, or uncertain significance are not included in this report.

Regulatory Disclosures

This test was developed and its performance validated by PCHS. The US Food and Drug Administration (FDA) has determined that clearance or approval of this method is not necessary and thus neither have been obtained. This test has been developed for clinical purposes. All test results are reviewed, interpreted and reported by our scientific and medical experts. To also exclude mistaken identity in your clinic, several guidelines recommend testing a second sample that is independently obtained from the proband. Please note that any further analysis will result in additional costs. The classification of variants can change over time.

Please feel free to contact PCHS (appointment@precheckhealth.com) in the future to determine if there have been any changes in classification of any reported variants.

Any preparation and processing of a sample from patient material provided to PCHS by a physician, clinical institute or a laboratory (by a "Partner") and the requested genetic and/or biochemical testing itself is based on the highest and most current scientific and analytical standards. However, in very few cases genetic or biochemical tests may not show the correct result, e.g. because of the quality of the material provided by a Partner to PCHS or in cases where any test provided by PCHS fails for unforeseeable or unknown reasons that cannot be influenced by PCHS in advance. In such cases, PCHS shall not be responsible and/or liable for the incomplete, potentially misleading or even wrong result of any testing if such issue could not be recognized by PCHS in advance.

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.

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