The BRCA2 c.2830A>T (p.Lys944Ter; p.K944*) variant has been reported in ClinVar as pathogenic by an expert panel and is classified by OncoKB as likely oncogenic with likely loss of function.1 This variant is present at very low frequency in gnomAD, with AF 1.06375e-05 (3/282020 alleles) in v2.1 and AF 3.71824e-06 (6/1613668 alleles) in v4.1, which is below ENIGMA BRCA2 BS1 and BA1 thresholds but means PM2 is not met because the variant is not absent from controls.2 This nonsense variant occurs in BRCA2 exon 11, a PVS1-eligible exon in the ENIGMA BRCA2 specification, and exon 11 protein termination codon variants are assigned PM5_Strong (PTC), supporting a loss-of-function interpretation.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.4
BRCA2
Final classification
Pathogenic
BRCA2 c.2830A>T · p.Lys944Ter
BRCA2
The BRCA2 c.2830A>T (p.Lys944Ter; p.K944*) variant has been reported in ClinVar as pathogenic by an expert panel and is classified by OncoKB as likely oncogenic with likely loss of function.
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules from final_classification_framework.
Classification rationale
PVS1PM5
Pathogenic
BRCA2 c.2830A>T
PVS1 + PM5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.71824e-06; MAF= 0.00037%, 6/1613668 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33461e-05; MAF= 0.00133%, 1/74928 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.06375e-05; MAF= 0.00106%, 3/282020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.02123e-05; MAF= 0.00402%, 1/24868 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,613,668
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
African/African American 1 / 74,928 |
0.0013% |
South Asian 1 / 91,010 |
0.0011% |
European (non-Finnish) 4 / 1,179,850 |
0.00034% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0011%
· 3 / 282,020
0 hom
0 hom
African/African American 1 / 24,868 |
0.004% |
South Asian 1 / 30,514 |
0.0033% |
European (non-Finnish) 1 / 128,752 |
0.00078% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Pathogenic (37 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66450359, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:16760289
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:23096105
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
Sources & reference links