The Clinical Significance of Unknown Sequence Variants in BRCA Genes

Calò, V

Risultato della ricerca: Article

19 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)-
Numero di pagine17
RivistaCancers
VolumeCancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644
Stato di pubblicazionePublished - 2010

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Missense Mutation
Alleles
Breast Neoplasms
BRCA1 Gene
Frameshift Mutation
Manuscripts
Germ-Line Mutation
Nonsense Codon
Amino Acid Substitution
Ovarian Neoplasms
Genes
Proteins
Databases

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cita questo

Calò, V (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. / Calò, V.

In: Cancers, Vol. Cancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644, 2010, pag. -.

Risultato della ricerca: Article

Calò, V 2010, 'The Clinical Significance of Unknown Sequence Variants in BRCA Genes', Cancers, vol. Cancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644, pagg. -.
Calò, V. The Clinical Significance of Unknown Sequence Variants in BRCA Genes. Cancers. 2010;Cancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644:-.
Calò, V. / The Clinical Significance of Unknown Sequence Variants in BRCA Genes. In: Cancers. 2010 ; Vol. Cancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644. pagg. -.
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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.",
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T1 - The Clinical Significance of Unknown Sequence Variants in BRCA Genes

AU - Calò, V

AU - Russo, Antonio

AU - Di Gaudio, Francesca

AU - Bruno, Loredana

AU - La Paglia, Laura

AU - Perez, Marco

AU - Margarese, Naomi

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - BRCA genes

UR - http://hdl.handle.net/10447/59689

M3 - Article

VL - Cancers 2010, 2, 1644-1660; doi:10.3390/cancers2031644

SP - -

JO - Cancers

JF - Cancers

SN - 2072-6694

ER -