The Clinical Significance of Unknown Sequence Variants in BRCA Genes

Valentina Calò,Naomi Margarese,Laura La Paglia,Antonio Russo,Francesca Di Gaudio,Loredana Bruno,Marco Perez

doi:10.3390/cancers2031644

Abstract

Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance.

Highlights

IntroductionThe identification of high penetrance alleles of the BRCA1 (MIM 113705) and BRCA2 (MIM600185) genes, which determine a high risk of developing hereditary breast and ovarian cancer, has made genetic testing an integral part of oncogenetic counseling in clinical practice [1,2,3,4,5,6].Such germline mutations lead to a risk of developing breast cancer of 45% at the age of 70 in BRCA1 carrier women and the risk of an ovarian neoplasia of about 40% at age 70, whereas in BRCA2 mutation carriers breast cancer risk is of 35% at age 70 and about 20% of ovarian cancer at age 70 [7].genes in the various hospital, research and private clinically certified genetic testing laboratories involved, leading to the identification of thousands of different mutations associated with the disease.The Breast Cancer Information Core Database (BIC database), a public archive of BRCA mutations, has collected the whole series of BRCA1 and BRCA2 coding variants, amounting up until now to about1,300 deleterious mutations in the two genes, identified from various population studies (Table 1).http://www.hgvs.org/mutnomen/Mutation nomenclature http://www.humgen.nl/mutalyzer/1.0.1/http://research.nhgri.nih.gov/bicCo-occurence in-trans www.dmubd.net www.agvgd.iarc.fr/index.phpSpecies conservation www.ebi.ac.uk/clustalw/index.html
600185) genes, which determine a high risk of developing hereditary breast and ovarian cancer, has made genetic testing an integral part of oncogenetic counseling in clinical practice [1,2,3,4,5,6]
BRCA1 carrier women and the risk of an ovarian neoplasia of about 40% at age 70, whereas in BRCA2 mutation carriers breast cancer risk is of 35% at age 70 and about 20% of ovarian cancer at age 70 [7]

Summary

Introduction

The identification of high penetrance alleles of the BRCA1 (MIM 113705) and BRCA2 (MIM600185) genes, which determine a high risk of developing hereditary breast and ovarian cancer, has made genetic testing an integral part of oncogenetic counseling in clinical practice [1,2,3,4,5,6].Such germline mutations lead to a risk of developing breast cancer of 45% at the age of 70 in BRCA1 carrier women and the risk of an ovarian neoplasia of about 40% at age 70, whereas in BRCA2 mutation carriers breast cancer risk is of 35% at age 70 and about 20% of ovarian cancer at age 70 [7].genes in the various hospital, research and private clinically certified genetic testing laboratories involved, leading to the identification of thousands of different mutations associated with the disease.The Breast Cancer Information Core Database (BIC database), a public archive of BRCA mutations, has collected the whole series of BRCA1 and BRCA2 coding variants, amounting up until now to about1,300 deleterious mutations in the two genes, identified from various population studies (Table 1).http://www.hgvs.org/mutnomen/Mutation nomenclature http://www.humgen.nl/mutalyzer/1.0.1/http://research.nhgri.nih.gov/bicCo-occurence in-trans www.dmubd.net www.agvgd.iarc.fr/index.phpSpecies conservation www.ebi.ac.uk/clustalw/index.html. 600185) genes, which determine a high risk of developing hereditary breast and ovarian cancer, has made genetic testing an integral part of oncogenetic counseling in clinical practice [1,2,3,4,5,6]. Such germline mutations lead to a risk of developing breast cancer of 45% at the age of 70 in BRCA1 carrier women and the risk of an ovarian neoplasia of about 40% at age 70, whereas in BRCA2 mutation carriers breast cancer risk is of 35% at age 70 and about 20% of ovarian cancer at age 70 [7].

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Conclusion