title: BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype.
abstract: We have investigated the clinical significance of the BRCA1 variant p.His1673del in 14 families from the Emilia-Romagna region of Italy, including 20 breast and 23 ovarian cancer cases; four families displayed site-specific ovarian cancer.The variant, absent in human variation databases, has been reported three times in BRCA1 specific databases; all probands shared the same rare haplotype at the BRCA1 locus, consistent with a common ancestor.The multifactorial likelihood method by Goldgar, used to estimate the probability of the variant being causative, gave a ratio of 2,263,474:1 in favor of causality. Moreover, in silico modeling suggested that His1673-lacking BRCA1 protein may have a decreased ability to bind BARD1 and other related proteins. All six ovarian carcinomas and two out of four breast carcinomas available showed a loss of the BRCA1 wild-type allele, which in three out of four ovarian carcinomas analyzed by FISH was associated with duplication of the chromosome 17 containing the variant. Although the pathogenicity of the allele is strongly supported by the multifactorial ratio,we cannot exclude that p.His1673del is not itself deleterious, but is linked to another undetected mutation on the same ancestral allele.
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca sui Tumori Ereditari, UO Genetica Medica, Università di Bologna, Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zuntini
authors.affiliation: Dipartimento di Oncologia ed Ematologia, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cortesi
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Calistri
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca sui Tumori Ereditari, UO Genetica Medica, Università di Bologna, Bologna, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: Biocomputing Group, BIGEA/Giorgio Prodi Interdepartmental Center for Cancer Research, Università di Bologna, Bologna, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Martelli
authors.affiliation: Biocomputing Group, BIGEA/Giorgio Prodi Interdepartmental Center for Cancer Research, Università di Bologna, Bologna, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
authors.affiliation: UO Anatomia Patologica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Capizzi
authors.affiliation: UO Anatomia Patologica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca sui Tumori Ereditari, UO Genetica Medica, Università di Bologna, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Miccoli
authors.affiliation: Dipartimento di Oncologia ed Ematologia, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Medici
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Dipartimento di Oncologia ed Ematologia, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Marchi
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zampiga
authors.affiliation: UO Anatomia Patologica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca sui Tumori Ereditari, UO Genetica Medica, Università di Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca sui Tumori Ereditari, UO Genetica Medica, Università di Bologna, Bologna, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Turchetti
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor
keywords: BRCA1; VUS; breast cancer; hereditary cancer; ovarian cancer