BRCA2breast cancer 2, early onset
Autism Reports / Total Reports
7 / 9Rare Variants / Common Variants
14 / 0Aliases
BRCA2, RP11-298P3.4, BRCC2, BROVCA2, FACD, FAD, FAD1, FANCB, FANCD, FANCD1, GLM3, PNCA2Associated Syndromes
-Chromosome Band
13q13.1Associated Disorders
-Relevance to Autism
Rare mutations in the BRCA2 gene have been identified in individuals with ASD (Neale et al., 2012).
Molecular Function
Inherited mutations in BRCA2 confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair.
External Links
SFARI Genomic Platforms
Reports related to BRCA2 (9 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Primary | Patterns and rates of exonic de novo mutations in autism spectrum disorders | Neale BM , et al. (2012) | Yes | - |
| 2 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
| 3 | Support | Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly | Rump P , et al. (2016) | No | Microcephaly |
| 4 | Support | Both rare and common genetic variants contribute to autism in the Faroe Islands | Leblond CS , et al. (2019) | Yes | - |
| 5 | Support | Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort | Wu H , et al. (2019) | Yes | Macrocephaly |
| 6 | Support | - | Zhou X et al. (2022) | Yes | - |
| 7 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
| 8 | Support | - | Amerh S Alqahtani et al. (2023) | Yes | - |
| 9 | Support | - | Axel Schmidt et al. (2024) | No | Cognitive impairment |
Rare Variants (14)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.6814A>G | p.Arg2272Gly | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.9383G>A | p.Arg3128Gln | missense_variant | De novo | - | - | 25363760 | De Rubeis S , et al. (2014) | |
| c.8351G>A | p.Arg2784Gln | missense_variant | Unknown | - | - | 39039281 | Axel Schmidt et al. (2024) | |
| c.8954-2A>G | - | splice_site_variant | Familial | Paternal | Simplex | 31674007 | Wu H , et al. (2019) | |
| c.7632C>T | p.Gly2544%3D | synonymous_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.6772G>A | p.Glu2258Lys | missense_variant | De novo | - | Simplex | 22495311 | Neale BM , et al. (2012) | |
| c.7316G>A | p.Gly2439Glu | missense_variant | De novo | - | Simplex | 22495311 | Neale BM , et al. (2012) | |
| c.9097dup | p.Thr3033AsnfsTer11 | frameshift_variant | Unknown | - | - | 39039281 | Axel Schmidt et al. (2024) | |
| c.9976A>T | p.Lys3326Ter | stop_gained | Familial | Paternal | Simplex | 30675382 | Leblond CS , et al. (2019) | |
| c.9672dup | p.Tyr3225IlefsTer30 | frameshift_variant | Familial | Both parents | Simplex | 26846091 | Rump P , et al. (2016) | |
| c.7300_7301del | p.Lys2434AlafsTer4 | frameshift_variant | Unknown | - | Unknown | 37799141 | Amerh S Alqahtani et al. (2023) | |
| c.5946del | p.Ser1982ArgfsTer22 | frameshift_variant | Familial | Paternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.658_659del | p.Val220IlefsTer4 | frameshift_variant | Familial | Paternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.10095_10096insT | p.Ser3366Ter | frameshift_variant | Familial | Maternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) |
Common Variants
No common variants reported.
SFARI Gene score
2
Strong Candidate
Two de novo missense variants in the BRCA2 gene were identified in ASD probands from the Simons Simplex Collection in PMID 22495311.
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
4/1/2022
3
2
Decreased from 3 to 2
Description
Two de novo missense variants in the BRCA2 gene were identified in ASD probands from the Simons Simplex Collection in PMID 22495311.
10/1/2019
4
3
Decreased from 4 to 3
New Scoring Scheme
Description
Two de novo missense variants in the BRCA2 gene were identified in ASD probands from the Simons Simplex Collection in PMID 22495311.
1/1/2019
4
4
Decreased from 4 to 4
Description
Two de novo missense variants in the BRCA2 gene were identified in ASD probands from the Simons Simplex Collection in PMID 22495311.
1/1/2016
4
4
Decreased from 4 to 4
Description
Two de novo missense variants in the BRCA2 gene were identified in ASD probands from the Simons Simplex Collection in PMID 22495311.
Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly.2016]7/1/2015
4
Increased from to 4
Description
Two de novo missense variants in the BRCA2 gene were identified in ASD probands from the Simons Simplex Collection in PMID 22495311.
Krishnan Probability Score
Score 0.3305532138086
Ranking 24829/25841 scored genes
[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser,
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.
ExAC Score
Score 2.2131212066187E-15
Ranking 17685/18225 scored genes
[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score
Score 0.95045021601255
Ranking 18497/18665 scored genes
[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score
Score 2
Ranking 376/461 scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.
Zhang D Score
Score -0.16450179620791
Ranking 14540/20870 scored genes
[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures),
or D score, was developed to combine evidence from de novo loss-of- function mutation with
evidence from cell-type- specific gene expression in the mouse brain (specifically translational
profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with
positive D scores are more likely to be associated with autism risk, with higher-confidence genes
having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204-
215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in
supplementary table 2 from that paper.
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| AARSD1 | alanyl-tRNA synthetase domain containing 1 | Human | Protein Binding | 80755 | Q9BTE6 |
| ATM | ataxia telangiectasia mutated | Human | Protein Modification | 472 | Q13315 |
| ATR | ataxia telangiectasia and Rad3 related | Human | Protein Modification | 545 | Q13535 |
| AURKB | aurora kinase B | Human | Protein Binding | 9212 | Q96GD4 |
| BACH1 | BTB and CNC homology 1, basic leucine zipper transcription factor 1 | Human | Protein Binding | 571 | O14867 |
| BAG4 | BCL2-associated athanogene 4 | Human | Protein Binding | 9530 | O95429 |
| BARD1 | BRCA1 associated RING domain 1 | Human | Protein Binding | 580 | A0AVN2 |
| BCCIP | BRCA2 and CDKN1A interacting protein | Human | Protein Binding | 56647 | Q9P287 |
| BRCA1 | breast cancer 1, early onset | Human | Protein Binding | 672 | P38398 |
| BRCC3 | BRCA1/BRCA2-containing complex, subunit 3 | Human | Protein Binding | 79184 | P46736 |
| C11orf30 | chromosome 11 open reading frame 30 | Human | Protein Binding | 56946 | Q7Z589 |
| C19ORF45 | Uncharacterized protein C19orf45 | Human | Protein Binding | 374877 | Q8NA69 |
| C6ORF141 | chromosome 6 open reading frame 141 | Human | Protein Binding | 135398 | Q5SZD1 |
| CCNA2 | cyclin A2 | Human | Protein Modification | 890 | P20248 |
| CCNB1 | cyclin B1 | Human | Protein Modification | 891 | P14635 |
| CCND1 | cyclin D1 | Human | Protein Binding | 595 | P24385 |
| CDK1 | cyclin-dependent kinase 1 | Human | Protein Modification | 983 | P06493 |
| CEBPA | CCAAT/enhancer binding protein (C/EBP), alpha | Human | DNA Binding | 1050 | P49715 |
| CEP55 | centrosomal protein 55kDa | Human | Protein Binding | 55165 | Q53EZ4 |
| CNKSR1 | Connector enhancer of kinase suppressor of ras 1 | Human | Protein Binding | 10256 | Q969H4 |
| DBP | D site of albumin promoter (albumin D-box) binding protein | Human | DNA Binding | 1628 | Q10586 |
| DMC1 | DMC1 dosage suppressor of mck1 homolog, meiosis-specific homologous recombination (yeast) | Human | Protein Binding | 11144 | Q14565 |
| DSN1 | DSN1, MIND kinetochore complex component, homolog (S. cerevisiae) | Human | Protein Binding | 79980 | Q9H410 |
| ERCC5 | excision repair cross-complementing rodent repair deficiency, complementation group 5 | Human | Protein Binding | 2073 | P28715 |
| FANCD2 | Fanconi anemia, complementation group D2 | Human | Protein Binding | 2177 | Q9BXW9 |
| FANCE | Fanconi anemia, complementation group E | Human | Protein Binding | 2178 | Q9HB96 |
| FANCG | Fanconi anemia, complementation group G | Human | Protein Binding | 2189 | O15287 |
| H2AFX | H2A histone family, member X | Human | Protein Binding | 3014 | P16104 |
| HMG20B | high mobility group 20B | Human | Protein Binding | 10362 | Q9P0W2 |
| HSPB8 | Human | Protein Binding | |||
| KAT2B | K(lysine) acetyltransferase 2B | Human | Protein Binding | 8850 | Q92831 |
| KIF23 | kinesin family member 23 | Human | Protein Binding | 9493 | Q02241 |
| KIF4A | kinesin family member 4A | Human | Protein Binding | 24137 | O95239 |
| L3MBTL1 | Lethal(3)malignant brain tumor-like protein 1 | Human | Protein Binding | 26013 | Q9Y468-1 |
| MIR1245A | microRNA 1245a | Human | DNA Binding | 100302219 | N/A |
| MLF1 | myeloid leukemia factor 1 | Human | Protein Binding | 4291 | P58340 |
| NSMCE4A | non-SMC element 4 homolog A (S. cerevisiae) | Human | Protein Binding | 54780 | Q9NXX6 |
| PALB2 | partner and localizer of BRCA2 | Human | Protein Binding | 79728 | Q86YC2 |
| PDCD6IP | programmed cell death 6 interacting protein | Human | Protein Binding | 10015 | Q8WUM4 |
| PDS5B | PDS5, regulator of cohesion maintenance, homolog B (S. cerevisiae) | Human | Protein Binding | 23047 | Q9NTI5 |
| PLK1 | polo-like kinase 1 | Human | Protein Modification | 5347 | P53350 |
| PMS1 | PMS1 postmeiotic segregation increased 1 (S. cerevisiae) | Human | Protein Binding | 5378 | P54277 |
| PMS2 | PMS2 postmeiotic segregation increased 2 (S. cerevisiae) | Human | Protein Binding | 5395 | P54278 |
| PPM1E | protein phosphatase, Mg2+/Mn2+ dependent, 1E | Human | Protein Binding | 22843 | Q8WY54 |
| PSMD3 | proteasome (prosome, macropain) 26S subunit, non-ATPase, 3 | Human | Protein Binding | 5709 | O43242 |
| PSMD6 | proteasome (prosome, macropain) 26S subunit, non-ATPase, 6 | Human | Protein Binding | 9861 | Q15008 |
| RABL2A | Rab-like protein 2A | Human | Protein Binding | 11159 | B7ZBD5 |
| RAD51 | RAD51 homolog (RecA homolog, E. coli) (S. cerevisiae) | Human | Protein Binding | 5888 | Q06609 |
| RFXANK | DNA-binding protein RFXANK | Human | Protein Binding | 8625 | O14593 |
| SHFM1 | split hand/foot malformation (ectrodactyly) type 1 | Human | Protein Binding | 7979 | P60896 |
| SKP2 | S-phase kinase-associated protein 2, E3 ubiquitin protein ligase | Human | Protein Binding | 6502 | B4DJT4 |
| SNX32 | Sorting nexin-32 | Human | Protein Binding | 254122 | Q86XE0 |
| SP1 | Sp1 transcription factor | Human | DNA Binding | 6667 | P08047 |
| SPANXA1 | sperm protein associated with the nucleus, X-linked, family member A1 | Human | Protein Binding | 30014 | Q9NS26 |
| STAT5A | signal transducer and activator of transcription 5A | Human | Protein Binding | 6776 | A8K6I5 |
| SYCP3 | synaptonemal complex protein 3 | Human | Protein Binding | 50511 | Q8IZU3 |
| TSG101 | tumor susceptibility gene 101 | Human | Protein Binding | 7251 | Q99816 |
| UQCC | ubiquinol-cytochrome c reductase complex chaperone | Human | Protein Binding | 55245 | Q9NVA1 |
| USP11 | ubiquitin specific peptidase 11 | Human | Protein Modification | 8237 | P51784 |
| WDR16 | WD repeat domain 16 | Human | Protein Binding | 146845 | Q8N1V2 |
| XRCC3 | X-ray repair complementing defective repair in Chinese hamster cells 3 | Human | Protein Binding | 7517 | O43542 |
| ZFP161 | zinc finger protein 161 homolog (mouse) | Human | DNA Binding | 7541 | O43829 |