BRCA1 p.His1673del is a pathogenic mutation associated with a predominant ovarian cancer phenotype.

Roberta Zuntini,Daniele Calistri,Pier Luigi Martelli,Rita Danesi,Simona Ferrari,Michelangelo Fiorentino,Isabella Marchi,Valentina Zampiga,Veronica Medici,Elisa Capizzi,Tommaso Pippucci,Laura Cortesi,Donatella Santini,Rita Casadio,Sara Miccoli,Daniela Turchetti

doi:10.18632/oncotarget.15151

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.

Highlights

In recent years, the detection of BRCA1 or 2 mutations in patients with breast cancer (BC) or ovarian cancer (OC) has become crucial to tailor their treatment, for instance through more extensive surgery and/or anti-neoplastic drugs that have proven to be effective in BRCA mutation carriers, such as PARPinhibitors [1]
The multifactorial likelihood method proposed by Goldgar, which has been adopted by the international consortia for Variants of Unknown Significance (VUS) classification [3, 4], provided a ratio of 2,263,474:1 in favor of causality
Concerning the former, only two out of 5 breast carcinomas with available information were hormone receptor negative, which is unusual for BRCA1 mutations

Summary

Introduction

The detection of BRCA1 or 2 mutations in patients with breast cancer (BC) or ovarian cancer (OC) has become crucial to tailor their treatment, for instance through more extensive surgery and/or anti-neoplastic drugs that have proven to be effective in BRCA mutation carriers, such as PARPinhibitors [1]. The request for BRCA1 and 2 genetic testing is rapidly increasing, as is the ability to satisfy these requests thanks to technological improvements, Generation Sequencing approaches. Such an increase in both the number and extension of tests (with NGS allowing the analysis of untranslated regions and deep intronic sequences) will result in an increased detection of Variants of Unknown Significance (VUS). A major advance in the classification of BRCA variants has been the www.impactjournals.com/oncotarget development of a multifactorial likelihood method that combines multiple independent factors to estimate the probability that a BRCA variant is pathogenic [3, 4]

Methods

Results

Conclusion