The Clinical Significance of Unknown Sequence Variants in BRCA Genes
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 co...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2010-09-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/2/3/1644/ |
| _version_ | 1797710646280716288 |
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| author | Antonio Russo Valentina Calò Loredana Bruno Laura La Paglia Marco Perez Naomi Margarese Francesca Di Gaudio |
| author_facet | Antonio Russo Valentina Calò Loredana Bruno Laura La Paglia Marco Perez Naomi Margarese Francesca Di Gaudio |
| author_sort | Antonio Russo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T06:55:13Z |
| format | Article |
| id | doaj.art-8e7cfc001d074acba83d499edb42f4a4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:55:13Z |
| publishDate | 2010-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8e7cfc001d074acba83d499edb42f4a42023-09-03T00:06:23ZengMDPI AGCancers2072-66942010-09-01231644166010.3390/cancers2031644The Clinical Significance of Unknown Sequence Variants in BRCA GenesAntonio RussoValentina CalòLoredana BrunoLaura La PagliaMarco PerezNaomi MargareseFrancesca Di GaudioGermline 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.http://www.mdpi.com/2072-6694/2/3/1644/BRCA genesvariantintegrated modelsoncogenetic counseling |
| spellingShingle | Antonio Russo Valentina Calò Loredana Bruno Laura La Paglia Marco Perez Naomi Margarese Francesca Di Gaudio The Clinical Significance of Unknown Sequence Variants in BRCA Genes Cancers BRCA genes variant integrated models oncogenetic counseling |
| title | The Clinical Significance of Unknown Sequence Variants in BRCA Genes |
| title_full | The Clinical Significance of Unknown Sequence Variants in BRCA Genes |
| title_fullStr | The Clinical Significance of Unknown Sequence Variants in BRCA Genes |
| title_full_unstemmed | The Clinical Significance of Unknown Sequence Variants in BRCA Genes |
| title_short | The Clinical Significance of Unknown Sequence Variants in BRCA Genes |
| title_sort | clinical significance of unknown sequence variants in brca genes |
| topic | BRCA genes variant integrated models oncogenetic counseling |
| url | http://www.mdpi.com/2072-6694/2/3/1644/ |
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