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.

Calò, V., Bruno, L., La Paglia, L., Perez, M., Margarese, N., Di Gaudio, F., et al. (2010). The Clinical Significance of Unknown Sequence Variants in BRCA Genes. CANCERS, Cancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644.

The Clinical Significance of Unknown Sequence Variants in BRCA Genes

BRUNO, Loredana;LA PAGLIA, Laura;PEREZ, Marco;MARGARESE, Naomi;DI GAUDIO, Francesca;RUSSO, Antonio
2010

Abstract

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.
Calò, V., Bruno, L., La Paglia, L., Perez, M., Margarese, N., Di Gaudio, F., et al. (2010). The Clinical Significance of Unknown Sequence Variants in BRCA Genes. CANCERS, Cancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644.
File in questo prodotto:
File Dimensione Formato  
cancers-02-01644.pdf

accesso aperto

Descrizione: Articolo
Dimensione 404.86 kB
Formato Adobe PDF
404.86 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/59689
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 26
  • ???jsp.display-item.citation.isi??? ND
social impact