GTS5:BRCA-related cancer predisposition syndrome (BRCA1, BRCA2) - Revision history

Kgeiersbach: references

2026-01-17T00:26:31Z

references

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 ==References==
-<ref name=":0" />Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [updated 2025 Mar 20]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301425.
+[[Category:GTS5]]
+[[Category:DISEASE]]
-<ref name=":1" />Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, Goldgar DE, Terry MB, Rookus MA, Easton DF, Antoniou AC; BRCA1 and BRCA2 Cohort Consortium; McGuffog L, Evans DG, Barrowdale D, Frost D, Adlard J, Ong KR, Izatt L, Tischkowitz M, Eeles R, Davidson R, Hodgson S, Ellis S, Nogues C, Lasset C, Stoppa-Lyonnet D, Fricker JP, Faivre L, Berthet P, Hooning MJ, van der Kolk LE, Kets CM, Adank MA, John EM, Chung WK, Andrulis IL, Southey M, Daly MB, Buys SS, Osorio A, Engel C, Kast K, Schmutzler RK, Caldes T, Jakubowska A, Simard J, Friedlander ML, McLachlan SA, Machackova E, Foretova L, Tan YY, Singer CF, Olah E, Gerdes AM, Arver B, Olsson H. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017 Jun 20;317(23):2402-2416. doi: 10.1001/jama.2017.7112. PMID: 28632866.
+<references />
 ==Notes==
 <nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 Prior Author(s):

Kgeiersbach: /* Primary Author(s)* */

2026-01-09T15:23:47Z

Primary Author(s)*

← Older revision		Revision as of 10:23, 9 January 2026
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	[[GTS5:Table_of_Contents\|Genetic Tumour Syndromes (Who Classification, 5th ed.)]]		[[GTS5:Table_of_Contents\|Genetic Tumour Syndromes (Who Classification, 5th ed.)]]
	==Primary Author(s)*==		==Primary Author(s)*==
	~~<br />~~Parisa Kargaran, Ph.D.		Parisa Kargaran, Ph.D.
	==WHO Classification of Disease==		==WHO Classification of Disease==

Kgeiersbach at 15:21, 9 January 2026

2026-01-09T15:21:24Z

Show changes

Parisa.Kargaran at 00:14, 18 December 2025

2025-12-18T00:14:23Z

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	'''Tumor testing:''' Tumor sequencing may identify somatic ''BRCA1/BRCA2'' alterations, loss of heterozygosity, or reversion mutations, which have implications for therapeutic selection and resistance, particularly in the context of PARP inhibitor therapy. Identification of a pathogenic ''BRCA1/BRCA2'' variant in tumor tissue should prompt confirmatory germline testing to distinguish hereditary from purely somatic events.		'''Tumor testing:''' Tumor sequencing may identify somatic ''BRCA1/BRCA2'' alterations, loss of heterozygosity, or reversion mutations, which have implications for therapeutic selection and resistance, particularly in the context of PARP inhibitor therapy. Identification of a pathogenic ''BRCA1/BRCA2'' variant in tumor tissue should prompt confirmatory germline testing to distinguish hereditary from purely somatic events.

	==Additional Information==		==Additional Information BRCA1 and BRCA2==
	~~Put your text here~~
			* '''Founder mutations:''' Multiple recurrent pathogenic variants demonstrate strong population specific founder effects, most notably c.68_69delAG (185delAG) and c.5266dupC (5382insC) in ''BRCA1'', and c.5946delT (6174delT) in ''BRCA2'', particularly among individuals of Ashkenazi Jewish ancestry. Additional founder variants have been reported in Icelandic, Dutch, and other geographically or ethnically defined populations, underscoring the importance of ancestry-informed testing strategies.

			* '''Genotype–phenotype correlations:''' Although penetrance is variable, ''BRCA1'' pathogenic variants are disproportionately associated with triple-negative breast cancer, whereas ''BRCA2'' pathogenic variants are more commonly linked to hormone receptor–positive breast cancer and confer a higher risk of male breast and prostate cancers. These genotype-phenotype differences have implications for clinical presentation, surveillance, and therapeutic decision-making.

			* '''Therapeutic implications:''' Tumors with biallelic inactivation of ''BRCA1'' or ''BRCA2'' exhibit homologous recombination deficiency (HRD), resulting in increased sensitivity to platinum-based chemotherapy and PARP inhibitors. However, acquisition of secondary somatic reversion mutations that restore gene function represents a well-established mechanism of acquired therapeutic resistance, particularly following prolonged treatment exposure.

			* '''Risk management considerations:''' Identification of germline pathogenic variants in ''BRCA1'' or ''BRCA2'' has substantial implications for personalized cancer risk assessment, implementation of enhanced surveillance protocols, consideration of risk-reducing surgical interventions, and cascade testing of at risk relatives.

			* '''Overlap with other syndromes:''' ''BRCA1'' and ''BRCA2'' associated hereditary cancer predisposition shares molecular and clinical features with other DNA damage response and homologous recombination repair disorders, including syndromes caused by pathogenic variants in ''PALB2, ATM, CHEK2,'' and ''RAD51C/D''. These genes should be considered in differential diagnosis and comprehensive hereditary cancer panel testing.

	==Links==		==Links==
	https://clinicalgenome.org/affiliation/50087/		https://clinicalgenome.org/affiliation/50087/

Parisa.Kargaran at 00:04, 18 December 2025

2025-12-18T00:04:42Z

← Older revision		Revision as of 19:04, 17 December 2025
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	==Genetic Diagnostic Testing Methods==		==Genetic Diagnostic Testing Methods==
	Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>		Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>

			Germline diagnosis of ''BRCA1'' and ''BRCA2'' associated hereditary cancer predisposition is established by molecular genetic testing performed on constitutional DNA (e.g., blood or saliva). Testing strategies must detect both sequence variants and copy number alterations, as pathogenic variants span multiple variant classes.

			'''Primary testing approaches:''' Next-generation sequencing (NGS), including multigene hereditary cancer panels or genome/exome sequencing, is the first-line method for detection of single-nucleotide variants (SNVs), small insertions/deletions, and splice-site variants in ''BRCA1'' and ''BRCA2''. Copy-number variant (CNV) analysis, performed using NGS-based CNV calling, multiplex ligation-dependent probe amplification (MLPA), or array-based methods, is required to detect large genomic rearrangements, including multi-exon deletions or duplications, which represent a clinically significant subset of pathogenic variants.

			'''Supplementary and confirmatory methods:''' MLPA or other targeted deletion/duplication assays are commonly used to confirm suspected CNVs or when sequencing-only approaches are insufficient. Sanger sequencing may be employed for targeted variant confirmation or cascade testing in at-risk relatives once a familial pathogenic variant has been identified.

			'''Tumor testing:''' Tumor sequencing may identify somatic ''BRCA1/BRCA2'' alterations, loss of heterozygosity, or reversion mutations, which have implications for therapeutic selection and resistance, particularly in the context of PARP inhibitor therapy. Identification of a pathogenic ''BRCA1/BRCA2'' variant in tumor tissue should prompt confirmatory germline testing to distinguish hereditary from purely somatic events.

	==Additional Information==		==Additional Information==
	Put your text here		Put your text here

Parisa.Kargaran at 23:55, 17 December 2025

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@@ Line 43: / Line 43: @@
 ==Epidemiology/Prevalence==
-Put your text here
 ==Genetic Abnormalities: Germline==
 Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.'')</span>

Parisa.Kargaran at 23:49, 17 December 2025

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← Older revision		Revision as of 18:49, 17 December 2025
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	==Links==		==Links==
	https://clinicalgenome.org/affiliation/50087/		https://clinicalgenome.org/affiliation/50087/

			https://www.ncbi.nlm.nih.gov/clinvar/?term=%22BRCA1%22%5BGENE%5D

			https://www.ncbi.nlm.nih.gov/clinvar/?term=%22BRCA2%22[GENE]

	==References==		==References==
	<ref name=":0" />Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [updated 2025 Mar 20]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301425.		<ref name=":0" />Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [updated 2025 Mar 20]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 20301425.

Parisa.Kargaran at 23:45, 17 December 2025

2025-12-17T23:45:08Z

← Older revision		Revision as of 18:45, 17 December 2025
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	==Definition/Description of Disease==		==Definition/Description of Disease==
	Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')</span>		Put your text here <span style="color:#0070C0">(''Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.'')</span>

			'''BRCA1 and BRCA2 Associated Hereditary Cancer Predisposition'''

			''BRCA1'' (17q21.31) and ''BRCA2'' (13q13.1) are tumor-suppressor genes that encode key components of the homologous recombination (HR) DNA double-strand break repair pathway. BRCA1 plays a central role in DNA damage sensing, checkpoint activation, and repair pathway choice, while ''BRCA2'' is essential for ''RAD51'' loading and stabilization at sites of DNA damage. Together, ''BRCA1'' and ''BRCA2'' maintain genomic stability and prevent accumulation of chromosomal aberrations. In the heterozygous state, germline pathogenic variants in ''BRCA1'' or ''BRCA2'' cause autosomal dominant hereditary breast and ovarian cancer (HBOC) syndrome with incomplete penetrance and variable expressivity. Affected individuals have substantially increased lifetime risks for female breast and ovarian cancers, with additional risks for male breast, prostate, pancreatic, and melanoma cancers, particularly in ''BRCA2'' carriers. Disease onset is often earlier than sporadic counterparts, and tumors frequently demonstrate a homologous recombination deficient (HRD) molecular phenotype. This syndrome is classified across multiple WHO Tumour Classification volumes under hereditary cancer predisposition syndromes affecting breast, ovary, prostate, and pancreas. In the biallelic state, pathogenic variants in ''BRCA2'' (also known as FANCD1) cause Fanconi anemia subtype D1, a rare autosomal recessive chromosomal instability disorder characterized by congenital anomalies, growth retardation, progressive bone marrow failure, and early onset malignancies, including acute leukemia and solid tumors in childhood. Biallelic pathogenic variants in ''BRCA1'' are exceedingly rare and have been associated with Fanconi anemia like phenotypes with developmental abnormalities and pediatric cancer susceptibility. These conditions fall within the WHO classification of inherited bone marrow failure and genomic instability syndromes. Diagnosis of ''BRCA1/BRCA2'' associated hereditary cancer predisposition is established through germline molecular genetic testing, typically using sequencing with deletion/duplication analysis. Tumor testing may reveal secondary somatic inactivation or reversion mutations, which have therapeutic implications. Differential diagnosis includes other hereditary breast and ovarian cancer syndromes involving genes in the HR and DNA damage response pathways (e.g., ''PALB2, ATM, CHEK2, RAD51C/D''), as well as sporadic cancers with somatic HR deficiency.

	==Epidemiology/Prevalence==		==Epidemiology/Prevalence==
	Put your text here		Put your text here

Parisa.Kargaran at 23:25, 17 December 2025

2025-12-17T23:25:04Z

Parisa.Kargaran at 21:43, 17 December 2025

2025-12-17T21:43:58Z

← Older revision		Revision as of 18:25, 17 December 2025
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	\|ATM; Inactivating mutations		\|ATM; Inactivating mutations
	\|DNA damage sensing and signaling (ATM–CHK2 pathway)		\|DNA damage sensing and signaling (ATM–CHK2 pathway)
	\|Impaired activation of DNA damage checkpoints, defective response to double-strand breaks, accumulation of genomic damage, and cancer predisposition		\|Impaired activation of DNA damage checkpoints, defective response to double-strand breaks, accumulation of genomic damage, and cancer predisposition<ref name=":16">Shiloh, Y., Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. ''Nat Rev Mol Cell Biol'' '''14''', 197–210 (2013). <nowiki>https://doi.org/10.1038/nrm3546</nowiki></ref>
	\|-		\|-
	\|CHEK2; Inactivating mutations		\|CHEK2; Inactivating mutations
	\|Cell-cycle checkpoint control and DNA damage response		\|Cell-cycle checkpoint control and DNA damage response
	\|Failure of G1/S and G2/M checkpoint arrest following DNA damage, allowing propagation of genomic instability		\|Failure of G1/S and G2/M checkpoint arrest following DNA damage, allowing propagation of genomic instability<ref name=":16" />
	\|-		\|-
	\|TP53; Inactivating or dominant-negative mutations		\|TP53; Inactivating or dominant-negative mutations
	\|Cell-cycle regulation, apoptosis, genome integrity		\|Cell-cycle regulation, apoptosis, genome integrity
	\|Loss of DNA damage–induced cell-cycle arrest and apoptosis, enabling survival and expansion of genetically unstable cells		\|Loss of DNA damage–induced cell-cycle arrest and apoptosis, enabling survival and expansion of genetically unstable cells<ref name=":5" /><ref name=":16" />
	\|-		\|-
	\|RAD51C / RAD51D; Inactivating mutations		\|RAD51C / RAD51D; Inactivating mutations
	\|Homologous recombination DNA repair		\|Homologous recombination DNA repair
	\|mpaired strand invasion and repair of DNA double-strand breaks, contributing to HRD and hereditary cancer susceptibility		\|mpaired strand invasion and repair of DNA double-strand breaks, contributing to HRD and hereditary cancer susceptibility<ref name=":0" /><ref name=":17">Loveday, C., Turnbull, C., Ramsay, E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43, 879–882 (2011). <nowiki>https://doi.org/10.1038/ng.893</nowiki></ref>
	\|}		\|}
	==Genetic Diagnostic Testing Methods==		==Genetic Diagnostic Testing Methods==
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	<ref name=":15" />Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21. PMID: 20858716; PMCID: PMC2948578.		<ref name=":15" />Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21. PMID: 20858716; PMCID: PMC2948578.

			<ref name=":16" />Shiloh, Y., Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14, 197–210 (2013). <nowiki>https://doi.org/10.1038/nrm3546</nowiki>

			<ref name=":17" />Loveday, C., Turnbull, C., Ramsay, E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43, 879–882 (2011). <nowiki>https://doi.org/10.1038/ng.893</nowiki>

	==Notes==		==Notes==

← Older revision		Revision as of 16:43, 17 December 2025
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	\|BRCA1; Loss-of-function germline or somatic mutations		\|BRCA1; Loss-of-function germline or somatic mutations
	\|Homologous recombination (HR) DNA double-strand break repair; DNA damage response		\|Homologous recombination (HR) DNA double-strand break repair; DNA damage response
	\|Defective DNA repair leading to genomic instability and chromosomal aberrations; increased cancer susceptibility. Tumors demonstrate homologous recombination deficiency (HRD) and sensitivity to platinum agents and PARP inhibitors		\|Defective DNA repair leading to genomic instability and chromosomal aberrations; increased cancer susceptibility. Tumors demonstrate homologous recombination deficiency (HRD) and sensitivity to platinum agents and PARP inhibitors<ref name=":0" /><ref name=":5" /><ref name=":10" />
	\|-		\|-
	\|BRCA2; Loss-of-function germline or somatic mutations		\|BRCA2; Loss-of-function germline or somatic mutations
	\|Homologous recombination DNA repair (RAD51 loading and stabilization)		\|Homologous recombination DNA repair (RAD51 loading and stabilization)
	\|Impaired repair of DNA double-strand breaks, genomic instability, and tumorigenesis; HRD phenotype with therapeutic vulnerability to PARP inhibition		\|Impaired repair of DNA double-strand breaks, genomic instability, and tumorigenesis; HRD phenotype with therapeutic vulnerability to PARP inhibition<ref name=":0" /><ref name=":5" /><ref name=":10" />
	\|-		\|-
	\|PALB2; Inactivating mutations		\|PALB2; Inactivating mutations
	\|BRCA1–BRCA2–PALB2 DNA repair complex (HR pathway)		\|BRCA1–BRCA2–PALB2 DNA repair complex (HR pathway)
	\|Disruption of BRCA1–BRCA2 interaction, defective homologous recombination, and increased cancer risk similar to BRCA2-associated tumors		\|Disruption of BRCA1–BRCA2 interaction, defective homologous recombination, and increased cancer risk similar to BRCA2-associated tumors<ref name=":0" /><ref name=":15">Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21. PMID: 20858716; PMCID: PMC2948578.</ref>
	\|-		\|-
	\|ATM; Inactivating mutations		\|ATM; Inactivating mutations
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	<ref name=":14" />Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008 Feb 28;451(7182):1111-5. doi: 10.1038/nature06548. Epub 2008 Feb 10. PMID: 18264088.		<ref name=":14" />Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008 Feb 28;451(7182):1111-5. doi: 10.1038/nature06548. Epub 2008 Feb 10. PMID: 18264088.

			<ref name=":15" />Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010 Oct 1;70(19):7353-9. doi: 10.1158/0008-5472.CAN-10-1012. Epub 2010 Sep 21. PMID: 20858716; PMCID: PMC2948578.

	==Notes==		==Notes==