Dataset Information

Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.

ABSTRACT: Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.

SUBMITTER: Whiley PJ

PROVIDER: S-EPMC3904950 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.

Whiley Phillip J PJ Parsons Michael T MT Leary Jennifer J Tucker Kathy K Warwick Linda L Dopita Belinda B Thorne Heather H Lakhani Sunil R SR Goldgar David E DE Brown Melissa A MA Spurdle Amanda B AB

PloS one 20140128 1

Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown ...[more]

PMID: 24489791

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Project description:BACKGROUND: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs) (variants with unknown clinical significance) and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis. METHODS: We analyzed 101 DNA samples from 79 breast/ovarian cancer families. The approach used is based on BRCA1 and BRCA2 sequence variants screening by SSCP or High-Resolution Melting (HRM) curve analysis followed by direct sequencing. In silico analyses have been performed using different bioinformatics programs to individualize genetics variations that can disrupt the BRCA1 and BRCA2 genes function. RESULTS: Among 80 UVs and polymorphisms detected in BRCA1/2 genes (33 BRCA1 and 47 BRCA2), 31 were new UVs (10 BRCA1 and 21 BRCA2), 7 were rare UVs (4 BRCA1 and 3 BRCA2) and 42 were polymorphic variants (19 BRCA1 and 23 BRCA2). Moreover, 8 new missense UVs identified in this study: two BRCA1 (c.4066C>A/p.Gln1356Lys, c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and six BRCA2 (c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys1290Ser, c.5428G>T/p.Val1810Phe, c.6346C>G/p.His2116Asp and c.9256G>A/p.Gly3086Arg) located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded by PolyPhen2 program and could be pathogenic. In addition, 5 new BRCA} missense UVs out of six that were found to be damaging by PolyPhen2 program, also were deleterious according to SIFT program. The rare BRCA1 UV c.5332G>A/p.Asp1778Asn was found here for the first time in co-occurrence in trans with the deleterious BRCA1 mutation c.798_799delTT/p.Ser267LysfsX19 in young breast cancer patient. Moreover, 10 new identified intronic variants with unknown clinical significance (3 BRCA1 and 7 BRCA2) in the present study, could be considered as benign, because GeneSplicer, SpliceSiteFinder and MaxEntScan prediction programs show no splice site alteration for these variants. Several missense polymorphisms of BRCA1 c.2612C>T/p.Pro871Leu, c.3548A>G/p.Lys1183Arg, c.4837A>G/p.Ser1613Gly and BRCA2 c.865A>C/p.Asn289His, c.1114A>C/p.Asn372His, c.2971A>G/p.Asn991Asp, c.7150C>A/p.Gly2384Lys have been identified with high frequency in patients who were tested negative for BRCA1 and BRCA2 mutations. These missense polymorphisms could have a role as susceptibility breast cancer markers in Algerian breast/ovarian cancer families where pathological BRCA1 and BRCA2 mutations were not present. CONCLUSIONS: For the first time, UVs and missense polymorphisms in BRCA1 and BRCA2 genes have been identified in Algerian breast/ovarian cancer families. Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs and common polymorphisms detected in our present work is on going in a larger study.

Project description:ImportanceThe clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines.ObjectiveTo evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 individuals across 14 cancer types.Design, setting, and participantsThis case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63 828 patients with 14 common cancer types and 37 086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021.Main outcomes and measuresGermline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls.ResultsA total of 65 108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17 911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P < 1 × 10-4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives.Conclusions and relevanceThe results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.

Project description:Mutations in BRCA1 and BRCA2 are responsible for a large proportion of breast-ovarian cancer families. Protein-truncating mutations have been effectively used in the clinical management of familial breast cancer due to their deleterious impact on protein function. However, the majority of missense variants identified throughout the genes continue to pose an obstacle for predictive informative testing due to low frequency and lack of information on how they affect BRCA1/2 function. Phosphorylation of BRCA1 and BRCA2 play an important role in their function as regulators of DNA repair, transcription and cell cycle in response to DNA damage but whether missense variants of uncertain significance (VUS) are able to disrupt this important process is not known. Here we employed a novel approach using NetworKIN which predicts in vivo kinase-substrate relationship, and evolutionary conservation algorithms SIFT, PolyPhen and Align-GVGD. We evaluated whether 191 BRCA1 and 43 BRCA2 VUS from the Breast Cancer Information Core (BIC) database can functionally alter the consensus phosphorylation motifs and abolish kinase recognition and binding to sites known to be phosphorylated in vivo. Our results show that 13.09% (25/191) BRCA1 and 13.95% (6/43) BRCA2 VUS altered the phosphorylation of BRCA1 and BRCA2. We highlight six BRCA1 (K309T, S632N, S1143F, Q1144H, Q1281P, S1542C) and three BRCA2 (S196I, T207A, P3292L) VUS as potentially clinically significant. These occurred rarely (n<2 in BIC), mutated evolutionarily conserved residues and abolished kinase binding to motifs established in the literature involved in DNA repair, cell cycle regulation, transcription or response to DNA damage. Additionally in vivo phosphorylation sites identified via through-put methods are also affected by VUS and are attractive targets for studying their biological and functional significance. We propose that rare VUS affecting phosphorylation may be a novel and important mechanism for which BRCA1 and BRCA2 functions are disrupted in breast cancer.

Dataset Information

Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.

Publications

Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.

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