The BRCA1 Variant p.Ser36Tyr Abrogates BRCA1 Protein Function and Potentially Confers a Moderate Risk of Breast Cancer

Christou, Charita M.; Hadjisavvas, Andreas; Kyratzi, Maria; Flouri, Christina; Neophytou, Ioanna; Anastasiadou, Violetta; Loizidou, Maria A.; Kyriacou, Kyriacos

doi:10.1371/journal.pone.0093400

Cited by 3 publications

(4 citation statements)

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“…The BRCA1 p.Ser36Tyr variant was identified in five female and a male BC patient from four unrelated families. Our group recently concluded that this BRCA1 variant demonstrates abrogated function and based on epidemiological, genetic and clinical data it is probably associated with a moderate BC risk (11).…”

Section: Resultsmentioning

confidence: 99%

“…In our patient cohort 33 VUS have been detected, with the majority of them being in the BRCA2 gene. In an attempt to categorize these variants, four different in silico assessment tools were applied . There was great degree of inconsistency between these predictions and hence it is impossible to draw definite conclusions on their pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

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BRCA1 and BRCA2 mutation testing in Cyprus; a population based study

et al. 2016

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This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast/ovarian cancer but were diagnosed with early onset breast cancer, ovarian cancer under the age of 60 or triple negative breast cancer. The spectrum of mutations identified in our patient cohort is different compared to other Mediterranean countries. Furthermore, several of the mutations detected are novel and have not been identified in other ethnic populations. This highlights the importance of operating a national reference center for cancer genetic diagnosis which offers services tailored to the needs of the Cypriot population.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 mutation testing in Cyprus; a population based study

et al. 2016

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“…It was estimated that the rare variant had a relative risk of above 2 and above 4 might confer moderate and high risk of breast cancer, respectively [ 26 , 27 ]. Our study suggests that one BRCA1 variant may be associated with increased risk of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study

Lai

Kang

et al. 2017

BMC Cancer

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BackgroundGenetic testing for BRCA1 and BRCA2 has led to the accurate identification of individuals at higher risk of cancer and the development of new therapies. Approximately 10-20% of the genetic testing for BRCA1 and BRCA2 leads to the identification of variants of uncertain significance (VUS), with higher proportions in Asians. We investigated the functional significance of 7 BRCA1 and 25 BRCA2 variants in a multi-ethnic Asian cohort using a case-control approach.MethodsThe MassARRAY genotyping was conducted in 1,394 Chinese, 406 Malay and 310 Indian breast cancer cases and 1,071 Chinese, 167 Malay and 255 Indian healthy controls. The association of individual variant with breast cancer risk was analyzed using logistic regression model adjusted for ethnicity, age and family history.ResultsOur study confirmed BRCA2 p.Ile3412Val is presented in >2% of unaffected women and is likely benign, and BRCA2 p.Ala1996Thr which is predicted to be likely pathogenic by in-silico models is presented in 2% of healthy Indian women suggesting that it may not be associated with breast cancer risk. Single-variant analysis suggests that BRCA1 p.Arg762Ser may be associated with breast cancer risk (OR = 7.4; 95% CI, 0.9–62.3; p = 0.06).ConclusionsOur study shows that BRCA2 p.Ile3412Val and p.Ala1996Thr are likely benign and highlights the need for population-specific studies to determine the likely functional significance of population-specific variants. Our study also suggests that BRCA1 p.Arg762Ser may be associated with increased risk of breast cancer but other methods or larger studies are required to determine a more precise estimate of breast cancer risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3099-6) contains supplementary material, which is available to authorized users.

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“…In addition, several of the previously published studies perform assays to study only one of the multiple functional characteristics of the BRCA1 protein separately, such as ubiquitination, transcriptional activation or homologous recombination repair (HRR). However, as BRCA1 VUSs are distributed throughout the entire protein including regions outside well-established domains, examining only a single assay may be misleading [23]. Hence, to clarify how variants in the more non-conserved parts of the protein can potentially affect its functions, there is a need for several functional assays utilising the full-length protein to mimic the more native state of the BRCA1 protein.…”

Section: Introductionmentioning

confidence: 99%

Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions

Hovland

Mchaina

Høberg-Vetti

et al. 2023

Genes

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The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in BRCA1 focus on variants located within the Really Interesting New Gene (RING), coiled-coil and BRCA1 C-terminal (BRCT) domains, and several missense variants in these regions have been shown to be pathogenic. However, the majority of these studies focus on domain specific assays, and have been performed using isolated protein domains and not the full-length BRCA1 protein. Furthermore, it has been suggested that BRCA1 missense variants located outside domains with known function are of no functional importance, and could be classified as (likely) benign. However, very little is known about the role of the regions outside the well-established domains of BRCA1, and only a few functional studies of missense variants located within these regions have been published. In this study, we have, therefore, functionally evaluated the effect of 14 rare BRCA1 missense variants considered to be of uncertain clinical significance, of which 13 are located outside the well-established domains and one within the RING domain. In order to investigate the hypothesis stating that most BRCA1 variants located outside the known protein domains are benign and of no functional importance, multiple protein assays including protein expression and stability, subcellular localisation and protein interactions have been performed, utilising the full-length protein to better mimic the native state of the protein. Two variants located outside the known domains (p.Met297Val and p.Asp1152Asn) and one variant within the RING domain (p.Leu52Phe) were found to make the BRCA1 protein more prone to proteasome-mediated degradation. In addition, two variants (p.Leu1439Phe and p.Gly890Arg) also located outside known domains were found to have reduced protein stability compared to the wild type protein. These findings indicate that variants located outside the RING, BRCT and coiled-coiled domains could also affect the BRCA1 protein function. For the nine remaining variants, no significant effects on BRCA1 protein functions were observed. Based on this, a reclassification of seven variants from VUS to likely benign could be suggested.

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The BRCA1 Variant p.Ser36Tyr Abrogates BRCA1 Protein Function and Potentially Confers a Moderate Risk of Breast Cancer

Cited by 3 publications

References 61 publications

BRCA1 and BRCA2 mutation testing in Cyprus; a population based study

BRCA1 and BRCA2 mutation testing in Cyprus; a population based study

Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study

Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions

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