LOVD - Legend for BRCA1


Sequence variations are described basically as recommended by the Ad-Hoc Nomenclature Committee of the Human Genome Variation Society (HGVS). For the most recent recommendations see the HGVS "Nomenclature for the description of sequence variants" web page. The most recent publication on the subject is by den Dunnen JT & Antonarakis SE (2000), Hum.Mut. 15: 7-12.

NOTE: in all cases, unless indicated otherwise, all data of an entry are as reported by the author(s)/submitter.

Path.: Variant pathogenicity, in the format Reported/Concluded; '+' indicating the variant is pathogenic, '+?' probably pathogenic, '-' no known pathogenicity, '-?' probably no pathogenicity, '?' effect unknown.

Exon: Standard BRCA1 (or BRCA2) exon numbering.

DNA change: Sequence variant name in HGVS cDNA sequence based nomenclature.

BIC DNA change: Sequence variant name in older BIC nomenclature.

Protein change: Sequence variant name in HGVS protein amino acid sequence based nomenclature. Predicted effect of change on protein (usually without experimental proof!)
  • ? = unknown
  • (0) = change expected to abolish translation
  • ?fs = frame shift, but observed phenotype does not fit with prediction (for instance less severe phenotype (BMD) observed, more severe phenotype (DMD) expected)
  • ?no fs = frame shift, but observed phenotype does not fit with prediction (for instance more severe phenotype (DMD) observed, less severe phenotype (BMD) expected)
  • del = causes deletion
  • fs = causes frame shift
  • fs? = effect on reading frame very likely (no experimental proof)
  • (fs?) = might affect the reading frame (no experimental proof)
  • no fs = does not cause frame shift
  • X = stop codon (nonsense)


Posterior P: Posterior probability in favor of pathogenicity.

IARC Class: Qualitative classification in the 5-grade IARC classification scheme.
Class Description Probability of being pathogenic
5 Definitely pathogenic
>0.99
4 Likely pathogenic
0.95-0.99
3 Uncertain
0.05-0.949
2 Likely not pathogenic or of little clinical significance
0.001-0.049
1 Not pathogenic or of no clinical significance
<0.001

  • 5 - Definitely pathogenic
  • 4 - Likely pathogenic
  • 3 - Uncertain
  • 2 - Likely not pathogenic or of little clinical significance
  • 1 - Not pathogenic or of no clinical significance

Key Observational Reference: Literature source - considered to be of primary importance - of observational data used in the integrated evaluation displayed here. Values are hyperlinked to PubMed.
  • Goldgar et al., AJHG 75: 535-544, 2004.
  • Tavtigian et al., Human Mutation 29: 1342-1354, 2008.
  • Wu, K. et al., Cancer Research 65: 417-426, 2005.
  • Tavtigian, S.V. et al., Journal of Medical Genetics 43: 295-305, 2006.
  • Chenevix-Trench, G. et al., Cancer Research 66: 2019-2027, 2006.
  • Spurdle AB et al., J Clin Oncol, 26: 1657-1663, 2008.
  • Easton DF et al., Am J Hum Genet, 81: 873-883, 2007.
  • Miki Y et al., Science, 266:66-71, 1994.
  • Spearman AD et al., J Clin Oncol, 26:5393-5400, 2008.
  • Sweet K et al., Breast Cancer Res Treat, 119:737-743, 2010.
  • Lovelock PK et al., J Med Genet, 43:74-83, 2006.
  • Osorio A et al., Hum Mutat, 28:477-485, 2007.
  • Tischkowitz M et al., Eur J Hum Genet, 16:820-832, 2008.
  • Walker LC et al., Human Mutation 31: E1484-E1505, 2010
  • Whiley et al., Human Mutation 32: 678-687, 2011
  • Domchek SM et al., Cancer Discov 3: 399-405 (2013).
  • Thomassen M et al., Breast Cancer Res Treat. 2012 Apr;132(3):1009-23.
  • Whiley PJ et al., PLoS One. 2014 Jan 28;9(1):e86836.

Prior P reference: Literature source of the sequence analysis based prior probability in favor of pathogenicity used in the integrated evaluation displayed here.
  • Goldgar et al., AJHG 75: 535-544, 2004.
  • Tavtigian et al., Human Mutation 29: 1342-1354, 2008.
  • Wu, K. et al., Cancer Research 65: 417-426, 2005.
  • Tavtigian, S.V. et al., Journal of Medical Genetics 43: 295-305, 2006.
  • Chenevix-Trench, G. et al., Cancer Research 66: 2019-2027, 2006.
  • Easton DF et al., Am J Hum Genet, 81: 873-883, 2007.
  • VallĂ©e et al., manuscript submitted, 2015

Missense analysis Prior P: This prior probability estimate combines position in the protein with an Align-GVGD based evaluation of missense substitutions that fall in the protein's key functional domains.

Splicing prior P: This prior probability estimate evaluates the sequence variant's probability to damage a splice donor, damage a splice acceptor, or create a de novo splice donor.

Other Prior P: Custom Priors other than missense or splice (full legend)

Combined prior P: The combined prior probability in favor of pathogenicity. is a combination of the missense analysis prior probability and the splicing analysis prior probability. Generally, it is the higher of the two sequence analysis-based prior probabilities.

Segregation LR: The likelihood ratio based on segregation analysis.

Pathology LR: The likelihood ratio based on tumor pathology and/ or tumor immunohistochemistry.

Sum Family LR: The likelihood ratio based on an analysis of the severity of summary family histories of breast and/ or ovarian cancer.

Co-occurrence LR: The likelihood ratio based on the frequency of co-occurrence between the variant of interest and clearly pathogenic variants in the same gene.

case-control LR: case-control likelihood ratios from the Illumina Collaborative Oncological Gene-environment Study array (full legend)

Product of LRs: The product of all of the likelihood ratios

Comments: to include additional refs/provenance and other warnings/additional relevant information

BRCA1 DB-ID: Database IDentifier; When available, links to OMIM ID's are provided.

Disease: Disease phenotype of the patient(s).

Reference: Literature reference with possible link to publication in PubMed, dbSNP entry or other online resource. "Submitted:" indicates that the mutation was submitted directly to this database by the laboratory indicated.

Template: Variant detected in DNA, RNA and/or Protein.
  • DNA
  • RNA
  • Protein

Technique: Technique used to reveal the change reported. For all methods, confirmation by sequencing (SEQ) is included. Select SEQ only when none of other techniques was used.
  • BESS = Base Excision Sequence Scanning
  • CMC = Chemical Mismatch Cleavage
  • DGGE = Denaturing-Gradient Gel-Electrophoresis
  • DHPLC = Denaturing High-Performance Liquid Chromatography
  • DOVAM = Detection Of Virtually All Mutations (SSCA variant)
  • DSCA = Double-Strand DNA Conformation Analysis
  • HD = HeteroDuplex analysis
  • IHC = Immuno-Histo-Chemistry
  • mPCR = multiplex PCR
  • MAPH = Multiplex Amplifiable Probe Hybridisation
  • MLPA = Multiplex Ligation-dependent Probe Amplification
  • PAGE = Poly-Acrylamide Gel-Electrophoresis
  • PCR = Polymerase Chain Reaction
  • PTT = Protein Truncation Test
  • RT-PCR = Reverse Transcription and PCR
  • SEQ = SEQuencing
  • Southern = Southern Blotting
  • SSCA = Single-Strand DNA Conformation Analysis (SSCP)
  • Western = Western Blotting

# Reported: Number of times this case has been reported