Multifactorial Likelihood Assessment of BRCA1 and BRCA2 Missense Variants Confirms That BRCA1:c.122A>G(p.His41Arg) Is a Pathogenic Mutation
Open accessAbstract
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.
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The BRCA2 variant lies in a highly conserved amino acid and is predicted to create a de novo donor splice-site in exon 17, but no experimental evidence supported this.
“The variant is in a highly conserved amino acid and is predicted to create a de novo donor splice-site in exon 17, although no experimental evidence supported this [14].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [14]
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- Authors
- Whiley, P. J., Parsons, M. T., Leary, J., Tucker, K., Warwick, L., Dopita, B., Thorne, H., Lakhani, S. R., Goldgar, D. E., Brown, M. A., & Spurdle, A. B.
- Affiliations
- The University of Queensland (AU)
- QIMR Berghofer Medical Research Institute (AU)
- The University of Sydney (AU)
- Prince of Wales Hospital (AU)
- Canberra Hospital (AU)
- Peter MacCallum Cancer Centre (AU)
- University of Utah (US)
- Corresponding author
- Spurdle, Amanda B.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-01-28
- Volume
- 9
- Issue
- 1
- Pages
- e86836
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3904950
- OpenAlex
- W2029088534
- Cited by
- 25
- References
- 48
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2020: 5 · 2019: 2 · 2018: 6 · 2017: 2 · 2016: 6 · 2015: 1
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- National Breast Cancer Foundation (CA116201)
- Cancer Australia (628333)
- National Institutes of Health (CA11620 1, CA116167)
- Medical Research Council (CA116201)
- National Health and Medical Research Council
- National Cancer Institute (CA116167, R01CA116167, CA116167Z, CA-116201, U01CA116167, P50CA116201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- BRCA1, BRCA2, missense mutations, pathogenicity assessment, RING domain, truncated protein, ubiquitin ligase activity, variant interpretation, genetic counseling, hereditary breast and ovarian cancer
- MeSH terms
- Exons, Humans, RNA, Messenger, Reproducibility of Results, Likelihood Functions, Sequence Deletion, Alternative Splicing, Computational Biology, BRCA1 Protein, Genetic Predisposition to Disease, Mutation, Missense, Multifactorial Inheritance, BRCA2 Protein
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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