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
Final classification
Benign
BS1BS3BP1BP5
BRCA1
c.1534C>T
p.Leu512Phe
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
BS1
Supporting
Benign
In gnomAD v2.1, the non-founder grpmax FAF is 8.82e-05, which is greater than the BS1_Supporting lower bound of 2e-05 and less than or equal to the BS1 threshold of 1e-04, supporting BS1_Supporting.
gnomAD v2.1 grpmax FAF 8.82e-05Highest observed population European (non-Finnish), a non-founder population
BS3
Strong
Benign
Specifications Table 9 lists BRCA1 c.1534C>T (p.(Leu512Phe)) as BS3 Strong because one calibrated study reported protein function similar to benign control variants.
Table 9 row: BS3 StrongBouwman 2020 (PMID:32546644) listed as likely neutral
BP1
Strong
Benign
Leu512 is outside the BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI is 0.00, which is less than or equal to the BP1_Strong splice threshold of 0.1; this supports BP1_Strong.
Protein change p.(Leu512Phe) at aa 512Domain definitions from BRCA1 appendicesSpliceAI max delta 0.00
BP5
Strong
Benign
Parsons supplementary data report a combined LR for causality of 0.007006151007218386, which is less than or equal to the ENIGMA BP5_Strong threshold of 0.05 and greater than the BP5_VeryStrong threshold of 0.00285, supporting BP5_Strong.
Combined LR 0.007006151007218386Posterior probability 0.0001429622324944735IARC Class Benign
Assessed · not applied
· 6 not met · 6 not assessed
Pathogenic
PS1
No retrieved evidence established that another pathogenic or likely pathogenic variant produces the same amino-acid change or the same predicted splice effect required for PS1 weighting.
PS3
A calibrated BRCA1 functional assay assigned BS3 rather than PS3, reporting protein function similar to benign control variants.
PS4
No case-control dataset meeting the ENIGMA BRCA1 PS4 requirement of statistically increased prevalence in affected individuals was retrieved for this variant.
PM2
PM2_Supporting requires absence from gnomAD, but the variant is present in gnomAD v2.1 at AF 3.54321e-05 with grpmax FAF 8.82e-05 and in gnomAD v4.1 at AF 0.000117733.
PM3
No evidence of biallelic BRCA1-related Fanconi anemia with PM3 point assignment was retrieved.
PP1
No quantitative co-segregation evidence supporting pathogenicity was retrieved for PP1.
PP3
For BRCA1, PP3 applies to missense variants inside a clinically important domain with BayesDel no-AF score >=0.28 or to variants with SpliceAI >=0.2.
PP4
The multifactorial likelihood data retrieved for this variant are against pathogenicity rather than meeting the PP4 thresholds for combined clinical evidence toward pathogenicity.
Benign
BA1
BA1 requires a non-founder FAF >0.001.
BS2
No unaffected adult or recessive-disease exclusion dataset meeting the BRCA1 BS2 point-based framework was retrieved.
BS4
The retrieved segregation LR is 0.99989998341, which is above the BS4_Supporting threshold of <=0.48 and therefore does not support lack of segregation.
BP7
No mRNA assay evidence demonstrating a benign transcript profile was retrieved for this missense variant, so BP7 was not applied.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6
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