BRCA1 c.1534C>T (p.Leu512Phe, p.L512F) has been shown in a calibrated functional assay to have protein function similar to benign control variants, supporting BS3_Strong.1 Multifactorial likelihood analysis yielded a combined LR for causality of 0.007006151007218386, which is below the ENIGMA BP5_Strong threshold of 0.05 and supports strong evidence against pathogenicity.2 The gnomAD v2.1 non-founder grpmax FAF is 8.82e-05, which is within the BS1_Supporting range of >2e-05 to <=1e-04, and the missense change lies outside the BRCA1 clinically important domains with SpliceAI 0.00, supporting BS1_Supporting and BP1_Strong benign evidence.3 Using the retrieved generic ACMG/AMP combination rules as fallback final-classification framework, the presence of at least two Strong benign criteria supports classification of this variant as Benign.4
BRCA1
Final classification
Benign
BRCA1 c.1534C>T · p.Leu512Phe
BRCA1
BRCA1 c.1534C>T (p.Leu512Phe, p.L512F) has been shown in a calibrated functional assay to have protein function similar to benign control variants, supporting BS3_Strong.
Generic ACMG/AMP final classification combination rules were used as the fallback framework because no explicit VCEP-specific final combination table was retrieved into the workspace; under the retrieved generic rules, two Strong benign criteria support a Benign classification.
Classification rationale
BS1BS3BP1BP5
Benign
BRCA1 c.1534C>T
BS1 + BS3 + BP1 + BP5
→
Benign
1
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
2
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
4
generic_acmg_combination_rules
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 4 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 benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000117733; MAF= 0.01177%, 190/1613824 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000192092; MAF= 0.01921%, 12/62470 alleles, homozygotes = 0); grpmax FAF= 0.00013243.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.54321e-05; MAF= 0.00354%, 10/282230 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76627e-05; MAF= 0.00777%, 10/128762 alleles, homozygotes = 0); grpmax FAF= 8.82e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.012%
· 190 / 1,613,824
0 hom · FAF 0.013%
0 hom · FAF 0.013%
Remaining individuals 12 / 62,470 |
0.019% |
European (non-Finnish) 178 / 1,179,972 |
0.015% |
+ 8 not observed (Admixed American, European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, African/African American, Amish)
gnomAD v2.1
0.0035%
· 10 / 282,230
0 hom · FAF 0.0088%
0 hom · FAF 0.0088%
European (non-Finnish) 10 / 128,762 |
0.0078% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV58794737, n = 4 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links