Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Hereditary Cancer in Clinical Practice
Published in: Hereditary Cancer in Clinical Practice 1/2016

Open Access 01-12-2016 | Research

When is a mutation not a mutation: the case of the c.594-2A>C splice variant in a woman harbouring another BRCA1 mutation in trans

Authors: Michelle Wong-Brown, Mary McPhillips, Margaret Gleeson, Allan D. Spigelman, Cliff J. Meldrum, Susan Dooley, Rodney J. Scott

Published in: Hereditary Cancer in Clinical Practice | Issue 1/2016

Login to get access

Abstract

Since the identification of BRCA1 there has only ever been described two bi-allelic mutation carriers, one of whom was subsequently shown to be a mono-allelic carrier. The second patient diagnosed with two BRCA1 mutations appears to be accurate but there remain some questions about the missense variant identified in that patient.
In this report we have identified a woman who is a bi-allelic mutation carrier of BRCA1 and provide an explanation as to why this patient has a phenotype very similar to that of any mono-allelic mutation carrier. The splice variant identified in this patient appears to be associated with the up-regulation of a BRCA1 splice variant that rescues the lethality of being a double mutant.
The consequences of the findings of this report may have implications for mutation interpretation and that could serve as a model for not only BRCA1 but also for other autosomal dominant disorders that are considered as being embryonically lethal.
Literature
1.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.CrossRefPubMed
2.
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998;62(3):676–89.PubMedCentralCrossRefPubMed
3.
4.
Spurdle AB, Healey S, Devereau A, Hogervorst FB, Monteiro AN, Nathanson KL, et al. ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat. 2012;33(1):2–7.PubMedCentralCrossRefPubMed
5.
Gorski B, Byrski T, Huzarski T, Jakubowska A, Menkiszak J, Gronwald J, et al. Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am J Hum Genet. 2000;66(6):1963–8.PubMedCentralCrossRefPubMed
6.
Domchek SM, Tang J, Stopfer J, Lilli DR, Hamel N, Tischkowitz M, et al. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov. 2013;3(4):399–405.PubMedCentralCrossRefPubMed
7.
Evers B, Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene. 2006;25(43):5885–97.CrossRefPubMed
8.
Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297(5581):606–9.CrossRefPubMed
9.
Boyd M, Harris F, McFarlane R, Davidson HR, Black DM. A human BRCA1 gene knockout. Nature. 1995;375(6532):541–2.CrossRefPubMed
10.
Kuschel B, Gayther SA, Easton DF, Ponder BA, Pharoah PD. Apparent human BRCA1 knockout caused by mispriming during polymerase chain reaction: implications for genetic testing. Genes Chromosomes Cancer. 2001;31(1):96–8.CrossRefPubMed
11.
Easton DF, Deffenbaugh AM, Pruss D, Frye C, Wenstrup RJ, Allen-Brady K, et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007;81(5):873–83.PubMedCentralCrossRefPubMed
12.
Sawyer SL, Tian L, Kähkönen M, Schwartzentruber J, Kircher M, University of Washington Centre for Mendelian Genomics, et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov, 2015;5(2):135-42.
13.
Vallon-Christersson J, Cayanan C, Haraldsson K, Loman N, Bergthorsson JT, Brøndum-Nielsen K, et al. Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families. Hum Mol Genet, 2001;10(4):353–60.CrossRefPubMed
14.
Orban TI, Olah E. Expression profiles of BRCA1 splice variants in asynchronous and in G1/S synchronized tumor cell lines. Biochem Biophys Res Commun. 2001;280(1):32–8.CrossRefPubMed
15.
16.
Rosenthal ET, Bowles KR, Pruss D, van Kan A, Vail PJ, McElroy H, et al. Exceptions to the rule: Case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes. Clin Genet. 2015. doi:10.​1111/​cge.​12560
17.
Whiley PJ, de la Hoya M, Thomassen M, Becker A, Brandão R, Pedersen IS, et al. Comparison of mRNA splicing assay protocols across multiple laboratories: Recommendations for best practice in standardized clinical testing. Mol Diag Genet. 2014;60(2):341-352.
18.
Tesoriero AA, Wong EM, Jenkins MA, Hopper JL, Brown MA, Chenevix-Trench G, et al. Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families. Hum Mutat. 2005;26(5):495.CrossRefPubMed
19.
Dosil V, Tosar A, Cañadas C, Pérez-Segura P, Díaz-Rubio E, Caldés T, et al. Alternative splicing and molecular characterization of splice site variants: BRCA1 c.591C>T as a case study. Clin Chem. 2010;56(1):53–61.CrossRefPubMed
Metadata
Title
When is a mutation not a mutation: the case of the c.594-2A>C splice variant in a woman harbouring another BRCA1 mutation in trans
Authors
Michelle Wong-Brown
Mary McPhillips
Margaret Gleeson
Allan D. Spigelman
Cliff J. Meldrum
Susan Dooley
Rodney J. Scott
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Hereditary Cancer in Clinical Practice / Issue 1/2016
Electronic ISSN: 1897-4287
DOI
https://doi.org/10.1186/s13053-015-0045-y

Other articles of this Issue 1/2016

Hereditary Cancer in Clinical Practice 1/2016 Go to the issue

Review

Cytotoxic and targeted therapy for hereditary cancers

Research

BRCA1 founder mutations do not contribute to increased risk of gastric cancer in the Polish population

Research

Clinical features and outcomes of germline mutation BRCA1-linked versus sporadic ovarian cancer patients

Case report

A novel deleterious c.2656G>T MSH2 germline mutation in a Pakistani family with a phenotypic overlap of hereditary breast and ovarian cancer and Lynch syndrome

Research

Intensive breast screening in BRCA2 mutation carriers is associated with reduced breast cancer specific and all cause mortality

Case report

An unusual case of Cowden syndrome associated with ganglioneuromatous polyposis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits