Human Gene Module / Chromosome 13 / BRCA2

BRCA2breast cancer 2, early onset

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 8
Rare Variants / Common Variants
12 / 0
Aliases
BRCA2, RP11-298P3.4,  BRCC2,  BROVCA2,  FACD,  FAD,  FAD1,  FANCB,  FANCD,  FANCD1,  GLM3,  PNCA2
Associated Syndromes
-
Chromosome Band
13q13.1
Associated 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.

SFARI Genomic Platforms
Reports related to BRCA2 (8 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 - et al. () Yes -
Rare Variants   (12)
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.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.7300_7301del p.Lys2434AlafsTer4 frameshift_variant Unknown - Unknown 37799141 et al. ()
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.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.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

2

Strong Candidate

See all Category 2 Genes

We 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
icon
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
icon
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
icon
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.

7/1/2015
icon
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.
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
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