BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype
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Roberta Zuntini1, Laura Cortesi2, Daniele Calistri3, Tommaso Pippucci1, Pier Luigi Martelli4, Rita Casadio4, Elisa Capizzi5, Donatella Santini5, Sara Miccoli1, Veronica Medici2, Rita Danesi3, Isabella Marchi2, Valentina Zampiga3, Michelangelo Fiorentino5, Simona Ferrari1, Daniela Turchetti1
1Dipartimento di Scienze Mediche e Chirurgiche, Centro di Ricerca sui Tumori Ereditari, UO Genetica Medica, Università di Bologna, Bologna, Italy
2Dipartimento di Oncologia ed Ematologia, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy
3Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
4Biocomputing Group, BIGEA/Giorgio Prodi Interdepartmental Center for Cancer Research, Università di Bologna, Bologna, Italy
5UO Anatomia Patologica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy
Daniela Turchetti, email: firstname.lastname@example.org
Keywords: BRCA1, ovarian cancer, hereditary cancer, VUS, breast cancer
Received: October 24, 2016 Accepted: January 26, 2017 Published: February 07, 2017
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.
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