Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer

Karppinen, Sanna-Maria; Heikkinen, Kaisa; Rapakko, Katrin; Winqvist, Robert

doi:10.1136/jmg.2004.020669

Cited by 78 publications

(81 citation statements)

References 41 publications

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“…None of the other variants identified here (that is, c.609A4C, c.1053G4C, c.1075del21 and c.1518C4T) was previously associated with an increased risk of breast cancer, 38,41 despite our results suggesting an association of the c.1518C4T (His506His) with an increased risk of breast cancer (P¼0.013), which is however not significant following Bonferroni correction. This finding would nonetheless have to be confirmed in much bigger cohorts.…”

Section: Brca1-interacting Gene Variants In Boc Families F Guénard Et Alcontrasting

confidence: 95%

“…34 The interaction of BRCA1 with RNA pol II 11 and DHX9 35 suggested a role for BARD1 in TCR. The BARD1 gene has been reported to be targeted by somatic 36 and germline [37][38][39] mutations in breast and in ovarian 36,40 cancer cohorts. BARD1 mutations have been identified in hereditary breast/ovarian cancers from BRCA1/2-negative patients 37,41 and it was suggested that the Cys557Ser variant may represent a low-penetrance breast cancer susceptibility allele.…”

Section: Introductionmentioning

confidence: 99%

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Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

et al. 2009

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Breast cancer is a heterogeneous disease displaying some degree of familial clustering. Highly penetrant breast cancer susceptibility genes represent approximately 20-25% of the familial aggregation of breast cancer. A significant proportion of this familial aggregation of breast cancer is thus yet to be explained by other breast cancer susceptibility genes. Given the high susceptibility conferred by the two major breast cancer predisposition genes, BRCA1 and BRCA2 and the implication of these genes in many key cellular processes, assessment of genes encoding BRCA1-interacting proteins as plausible breast cancer candidate genes is thus attractive. In this study, four genes encoding BRCA1-interacting proteins were analyzed in a cohort of 96 breast cancer individuals from high-risk non-BRCA1/BRCA2 French Canadian families. Although no deleterious truncating germline mutations or aberrant spliced mRNA species were identified, a total of 10, 4, 11 and 6 variants were found in the AURKA, BAP1, BARD1 and DHX9 genes, respectively. The allele frequency of each variant was further ascertained in a cohort of 98 healthy French Canadian unrelated women and a difference in allele frequency was observed for one BARD1 variant based on single-marker analysis. Haplotype estimation, haplotype blocks and tagging SNPs identification were then performed for each gene, providing a valuable tool for further searches of common disease-associated variants in these genes and therefore further analyses on these genes in larger cohorts is warranted in the search of low-to-moderate penetrance breast cancer susceptibility alleles.

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Section: Brca1-interacting Gene Variants In Boc Families F Guénard Et Alcontrasting

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

et al. 2009

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“…Mutation reports about BARD1 mention mostly missense mutations, a few silent mutations and one in-frame deletion [Thai et al, 1998;Ghimenti et al, 2002;Ishitobi et al, 2003;Karppinen et al, 2004;Sauer and Andrulis, 2005;Vahteristo et al, 2006;Huo et al, 2007;Gorringe et al, 2008], but obvious deleterious BARD1 germline mutations (e.g. protein truncating mutations) have not been found till now.…”

Section: Discussionmentioning

confidence: 99%

“…The p.Arg658Cys variant has been reported by three other groups. Thai and collaborators [1998] showed its presence in 1% of the Caucasian population, while Karppinen et al [2004] and Vahteristo et al [2006] reported this variant in respectively 3.2% and 1.9% of their Finnish familial cases but with equal frequencies observed in their controls. A possible explanation for this discrepancy could be a biased selection of our control samples.…”

Section: Discussionmentioning

confidence: 99%

Cancer predisposing missense and protein truncatingBARD1mutations in non-BRCA1orBRCA2breast cancer families

et al. 2010

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Fifteen years ago BRCA1 and BRCA2 were reported as high penetrant breast cancer predisposing genes. However, mutations in these genes are found in only a fraction of high risk families. BARD1 is a candidate breast cancer gene, but only a limited number of missense mutations with rather unclear pathogenic consequences have been reported. We screened 196 high risk breast cancer families for the occurrence of BARD1 variants. All genetic variants were analyzed using clinical information as well as IN SILICO predictive tools, including protein modeling. We found three candidate pathogenic mutations in seven families including a first case of a protein truncating mutation (p.Glu652fs) removing the entire second BRCT domain of BARD1. In conclusion, we provide evidence for an increased breast cancer risk associated to specific BARD1 germline mutations. However, these BARD1 mutations occur in a minority of hereditary breast cancer families.

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“…Cys557Ser was suggested to increase familial breast cancer risk by fourfold, 13 and the Val507Met was associated with a two-fold elevation in postmenopausal breast cancer risk. 14 We evaluated these variants in extensive series of unselected and familial breast cancer patients, and healthy controls.…”

Section: Introductionmentioning

confidence: 99%

BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition

et al. 2005

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BARD1 (BRCA1-associated RING-domain 1) is a tumor suppressor whose protein product interacts with BRCA1, and in which rare somatic and germline mutations have been reported in breast, uterine, and endometrial cancers. We aimed to evaluate whether there are BARD1 genetic variants that contribute to breast cancer risk by screening the gene for germline alterations in 45 Finnish familial breast cancer patients and in seven patients with both breast and ovarian cancer. Two of the missense alterations identified (Cys557Ser and Val507Met) were recently suggested to associate with an increased breast cancer risk. We also analyzed these variants in large and independent series of familial and unselected breast cancer patients and healthy controls. No clearly deleterious mutations were detected in the initial mutation screening. No association of the Cys557Ser and breast cancer risk was observed as the variant was found altogether in 1.4% (16/1181) of familial and 2.2% (34/1565) of unselected breast cancer patients, and in 2.5% (27/1083) of healthy controls. The frequency of the Val-allele of the Val507Met variant was modestly higher among breast cancer patients than among healthy controls, although the difference did not reach statistical significance. No statistically significant association of the Cys557Ser or Val507Met variants with any clinicopathologic parameters was observed. These results suggest that the contribution of the BARD1 germline variants to breast cancer predisposition is very limited, and that neither Cys557Ser nor Val507Met have an effect on familial breast cancer susceptibility.

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Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer

Cited by 78 publications

References 41 publications

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

Cancer predisposing missense and protein truncatingBARD1mutations in non-BRCA1orBRCA2breast cancer families

BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition

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