Truncating mutations are the most frequent mutations seen in BRCA2. The two functional nuclear localization signals (NLSs) in BRCA2 localize to the final 156 amino acids in BRCA2. NLS1 maps to amino acids 3263-3269, while NLS2 maps to residues 3381-3385. Both NLSs are functional, but only NLS1 is essential for BRCA2 translocation to the nucleus (Spain et al. 1999, Yano et al. 2000). A common cancer mutant BRCA2 F2058Lfs*12 (c.6174delT) is cytoplasmic, as well as the BRCA2 K3263* mutant generated by directed mutagenesis (Spain et al. 1999). BRCA2 polymorphisms that result in prematurely truncated proteins with intact NLS1, BRCA2 K3326* and BRCA2 E3342*, are not associated with cancer and the two truncated proteins are properly localized (Spain et al. 1999). As BRCA2 F2058Lfs*12 (c.6174delT) lacks the SEM1 (DSS1) binding region, which lies between amino acids 2457 2800 of BRCA2, it is annotated in the context of loss of SEM1 binding function (binding to SEM1 promotes nuclear localization of BRCA2). BRCA2 frameshift mutant BRCA2 D2983Ffs*34, detected in familial breast cancer, was shown to be almost exclusively cytosolic, as expected (Ma et al. 2017).

BRCA2 nonsense mutants, frameshift insertion mutants, and frameshift deletion mutants listed below have not been functionally studied but are annotated as candidate nuclear translocation defective mutants based on the fact that they lack at least the final 156 amino acids in their C-terminus (that is, the truncation occurs before the amino acid residue 3263, which is the first amino acid in NLS1). Based on the standards and guidelines for the interpretation of sequence variants issued by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Richards et al. 2015), these mutants satisfy the criterion PM1 for the moderate evidence of pathogenicity (mutations located in a mutational hotspot and/or critical and well-established functional domain without benign variation). Truncating mutations that occur N-terminally to the BRCA2 region involved in binding to SEM1 (DSS1) (amino acid residues 2457-2800 of BRCA2), which precedes nuclear transport, are annotated in the context of the loss of SEM1 binding function.

The following BRCA2 nonsense mutants that contain the SEM1-binding region lack the NLS:
BRCA2 E2474*
BRCA2 E2476*
BRCA2 R2520*
BRCA2 K2555*
BRCA2 K2570*
BRCA2 E2571*
BRCA2 W2586*
BRCA2 G2593*
BRCA2 E2599*
BRCA2 R2625*
BRCA2 S2695*
BRCA2 L2696*
BRCA2 Q2731*
BRCA2 Q2749*
BRCA2 Q2823*
BRCA2 S2835*
BRCA2 G2837*
BRCA2 E2863*
BRCA2 Q2870*
BRCA2 E2872*
BRCA2 Y2884*
BRCA2 E2906*
BRCA2 L2926*
BRCA2 E2956*
BRCA2 E2959*
BRCA2 W2970*
BRCA2 Y2977*
BRCA2 S2978*
BRCA2 S2994*
BRCA2 Y2997*
BRCA2 Y3006*
BRCA2 K3015*
BRCA2 Q3026*
BRCA2 K3032*
BRCA2 Q3036*
BRCA2 E3053*
BRCA2 Q3066*
BRCA2 E3071*
BRCA2 E3111*
BRCA2 R3128*
BRCA2 S3231*
BRCA2 S3245*

The following BRCA2 frameshift insertion mutants that contain the SEM1-binding region lack the NLS:
BRCA2 R2502Lfs*24
BRCA2 T2515Nfs*24
BRCA2 T2517Hfs*22
BRCA2 I2675Dfs*6
BRCA2 R2787Lfs*35
BRCA2 E2847*
BRCA2 E2981Rfs*37
BRCA2 T3033Nfs*11
BRCA2 T3085Nfs*26
BRCA2 S3144Ffs*6
BRCA2 F3159Ifs*9

The following BRCA2 frameshift deletion mutants that contain the SEM1-binding region lack the NLS:
BRCA2 N2553Tfs*95
BRCA2 N2556Mfs*92
BRCA2 P2608Qfs*40
BRCA2 R2645Nfs*3
BRCA2 K2674Rfs*2
BRCA2 T2685Hfs*9
BRCA2 S2697Kfs*31
BRCA2 V2716Wfs*17
BRCA2 L2745Qfs*31
BRCA2 G2760Pfs*13
BRCA2 T2766Nfs*11
BRCA2 P2767Lfs*10
BRCA2 V2969Cfs*7
BRCA2 E2981Kfs*7
BRCA2 T3033Lfs*29
BRCA2 C3069Lfs*5
BRCA2 T3085Qfs*19
BRCA2 P3089Lfs*15
BRCA2 N3164Ifs*53
BRCA2 L3172Afs*44
BRCA2 C3198Yfs*23
BRCA2 R3237Gfs*12
BRCA2 E3256Rfs*19
BRCA2 K3263Rfs*12