Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function of BRCA1 in PALB2 binding

Stable Identifier
R-HSA-9701199
Type
Reaction [transition]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function of BRCA1 in PALB2 binding
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The following missense mutants of BRCA1, reported in cancer, contain mutations in the second coiled coil domain, essential for binding to PALB2 (residues 1397-1424). They have been shown to be impaired in their ability both to bind to PALB2 and to rescue the gene conversion defect associated with BRCA1 depletion:
BRCA1 M1400V (Sy et al. 2009: partial loss of function)
BRCA1 L1407P (Sy et al. 2009); this mutation has also been modelled in mice, recapitulating the human Fanconi anemia phenotype (Park et al. 2020)
BRCA1 M1411T (Sy et al. 2009).

BRCA1 single nucleotide variants located in splicing regulatory regions have the potential to disrupt mRNA splicing and generate frameshift or in-frame proteins lacking functional domains. In this sense, several BRCA1 splicing mutations have been identified in hereditary breast/ovarian cancer cases and predicted to produce non-functional proteins that would lack the coiled-coil and BRCT domains. All variants are derived from ClinVar database (Landrum et al. 2018) and have been classified as pathogenic by expert panels. Variants are listed below and annotated according to the reference transcript NM_007294, but their annotation at the protein level is currently outside the scope of Reactome database:
c.135-1G>T
c.212+1G>A
c.212+1G>T
c.302-1G>C
c.302-2del
c.441+2T>G
c.4097-1G>A
c.4097-2A>G
c.4185+2_4185+22delinsA
c.4357+1G>A
c.4357+1G>T
c.4358_4484del127
c.4484+1del
c.4485-1G>T
c.4675+1G>A
c.4676-1G>A
c.4987-1G>A
c.4987-2A>G
c.547+1G>T
c.547+2T>A
c.5074+1G>A
c.5074+1G>T
c.5074+2T>C
c.5152+1G>T
c.5153-1G>A
c.5153-1G>C
c.5155delG
c.5155dup
c.5277+1_5277+6del
c.5277+1G>A
c.5278-2del
c.5331_5332+1delinsCAACAT
c.5332+1G>A
c.5468-1G>A

Many nonsense and frameshift mutants of BRCA1 reported in cancer result in prematurely truncated proteins. These mutant proteins resemble the synthetic BRCA1 fragment consisting of amino acids 1-1314, which is unable to interact with PALB2 (Sy et al. 2009). These BRCA1 truncation mutants are likely impaired in some of the other steps of DNA double-strand break repair (DSBR) that precede PALB2 binding but their effect on DSBR has not been comprehensively tested.

The following functionally uncharacterized nonsense mutants of BRCA1 , derived from COSMIC database (Forbes et al. 2017), which are truncated before the amino acid position 1314, have been annotated as candidates:
BRCA1 Q94*
BRCA1 E111*
BRCA1 E116*
BRCA1 Q126*
BRCA1 E149*
BRCA1 Q169*
BRCA1 Q202*
BRCA1 Q210*
BRCA1 E272*
BRCA1 Q317*
BRCA1 W372*
BRCA1 R388*
BRCA1 L431*
BRCA1 S451*
BRCA1 E457*
BRCA1 K467*
BRCA1 L474*
BRCA1 E515*
BRCA1 K519*
BRCA1 G535*
BRCA1 Q541*
BRCA1 Q544*
BRCA1 E572*
BRCA1 E577*
BRCA1 E597*
BRCA1 E648*
BRCA1 Y655*
BRCA1 Q667*
BRCA1 E673*
BRCA1 E720*
BRCA1 E733*
BRCA1 Y777*
BRCA1 E787*
BRCA1 K800*
BRCA1 E836*
BRCA1 E842*
BRCA1 E848*
BRCA1 S864*
BRCA1 E881*
BRCA1 E904*
BRCA1 G911*
BRCA1 Q934*
BRCA1 K935*
BRCA1 S988*
BRCA1 E1004*
BRCA1 S1007*
BRCA1 S1009*
BRCA1 E1033*
BRCA1 K1037*
BRCA1 E1107*
BRCA1 E1112*
BRCA1 Q1144*
BRCA1 K1160*
BRCA1 E1167*
BRCA1 R1203*
BRCA1 E1210*
BRCA1 E1214*
BRCA1 Q1240*
BRCA1 E1250*
BRCA1 E1258*
BRCA1 L1276*
BRCA1 Q1281*

The following functionally uncharacterized frameshift mutants of BRCA1 , derived from COSMIC database (Forbes et al. 2017), which are truncated before the amino acid position 1314, have been annotated as candidates:
BRCA1 R71Kfs*10
BRCA1 E75Kfs*13
BRCA1 V83Cfs*2
BRCA1 E111Gfs*3
BRCA1 P115*
BRCA1 Q172Nfs*62
BRCA1 Q210Sfs*6
BRCA1 A224Gfs*4
BRCA1 S242Rfs*5
BRCA1 N287Qfs*6
BRCA1 L290Yfs*8
BRCA1 D295Tfs*3
BRCA1 K339Rfs*2
BRCA1 V340Gfs*6
BRCA1 W372Yfs*5
BRCA1 S426*
BRCA1 H437*
BRCA1 R446Sfs*9
BRCA1 E453Rfs*22
BRCA1 T464Pfs*11
BRCA1 L502Afs*2
BRCA1 A521Qfs*11
BRCA1 N555Ifs*17
BRCA1 N555Kfs*17
BRCA1 N567Pfs*16
BRCA1 K608Ifs*3
BRCA1 K654Sfs*47
BRCA1 Y655Vfs*18
BRCA1 L668Pfs*33
BRCA1 E686*
BRCA1 N714Kfs*4
BRCA1 P724Lfs*12
BRCA1 E729Rfs*10
BRCA1 K739Ifs*15
BRCA1 V757Ffs*8
BRCA1 G813Dfs*2
BRCA1 H816Qfs*3
BRCA1 G817Vfs*29
BRCA1 F869Vfs*35
BRCA1 A878Gfs*24
BRCA1 S886Cfs*16
BRCA1 K893Rfs*107
BRCA1 K894Tfs*8
BRCA1 P897Kfs*5
BRCA1 N909Kfs*6
BRCA1 G911Efs*89
BRCA1 T922Lfs*77
BRCA1 I925Nfs*13
BRCA1 G928Afs*72
BRCA1 G948Efs*52
BRCA1 I986Sfs*14
BRCA1 F989Lfs*10
BRCA1 F989Lfs*11
BRCA1 E1013Nfs*4
BRCA1 N1029Kfs*3
BRCA1 N1045*
BRCA1 K1079Nfs*2
BRCA1 L1086Dfs*2
BRCA1 E1112Dfs*5
BRCA1 E1115*
BRCA1 N1121Kfs*12
BRCA1 Y1127Sfs*6
BRCA1 C1146Lfs*8
BRCA1 D1156Cfs*2
BRCA1 V1176Ffs*34
BRCA1 K1183Rfs*4
BRCA1 R1188Efs*3
BRCA1 S1217Rfs*21
BRCA1 E1219Ffs*12
BRCA1 C1225Sfs*10
BRCA1 K1254Nfs*11
BRCA1 N1265Kfs*4
BRCA1 E1282Afs*26
BRCA1 H1284Tfs*23
BRCA1 E1288Kfs*19
Literature References
PubMed ID Title Journal Year
19369211 PALB2 is an integral component of the BRCA complex required for homologous recombination repair

Sy, SM, Huen, MS, Chen, J

Proc Natl Acad Sci U S A 2009
29165669 ClinVar: improving access to variant interpretations and supporting evidence

Landrum, MJ, Lee, JM, Benson, M, Brown, GR, Chao, C, Chitipiralla, S, Gu, B, Hart, J, Hoffman, D, Jang, W, Karapetyan, K, Katz, K, Liu, C, Maddipatla, Z, Malheiro, A, McDaniel, K, Ovetsky, M, Riley, G, Zhou, G, Holmes, JB, Kattman, BL, Maglott, DR

Nucleic Acids Res 2018
27899578 COSMIC: somatic cancer genetics at high-resolution

Forbes, SA, Beare, D, Boutselakis, H, Bamford, S, Bindal, N, Tate, J, Cole, CG, Ward, S, Dawson, E, Ponting, L, Stefancsik, R, Harsha, B, Kok, CY, Jia, M, Jubb, H, Sondka, Z, Thompson, S, De, T, Campbell, PJ

Nucleic Acids Res. 2017
32732220 Ablation of the Brca1-Palb2 Interaction Phenocopies Fanconi Anemia in Mice

Park, D, Bergin, SM, Jones, D, Ru, P, Koivisto, CS, Jeon, YJ, Sizemore, GM, Kladney, RD, Hadjis, A, Shakya, R, Ludwig, T

Cancer Res 2020
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Normal reaction
D-loop formation mediated by PALB2, BRCA2 and RAD51 (Homo sapiens)
Functional status

Loss of function and partial loss of function of Defective 3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:p-T309-RAD51:p-T3387-BRCA2:BCDX2 complex [nucleoplasm]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cross References
Mondo
Authored
Orlic-Milacic, M  (2020-10-15)
Reviewed
Montalban, G  (2021-08-09)
Masson, JY  (2021-08-09)
Created
Orlic-Milacic, M  (2020-09-24)
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