Variant classification summary

NM_007294.4:c.1534C>T

BRCA1 · NP_009225.1:p.(Leu512Phe) · NM_007294.4

GRCh37: chr17:41246014 G>A · GRCh38: chr17:43093997 G>A

Gene: BRCA1 Transcript: NM_007294.4

Final call

Benign

BS3_Strong BP5_Strong BP1_Strong BS1_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Leu512Phe)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

Final determination:

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_007294.4:c.1534C>T is a missense substitution, p.(Leu512Phe), and is not a null, canonical splice-site, initiation-codon, or exon deletion variant.	cspec
PS1	Not assessed	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.	cspec
PS2	N/A	PS2 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
PS3	Not met	A calibrated BRCA1 functional assay assigned BS3 rather than PS3, reporting protein function similar to benign control variants.	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
PS4	Not assessed	No case-control dataset meeting the ENIGMA BRCA1 PS4 requirement of statistically increased prevalence in affected individuals was retrieved for this variant.	cspec
PM1	N/A	PM1 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
PM2	Not met	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.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence of biallelic BRCA1-related Fanconi anemia with PM3 point assignment was retrieved.	cspec
PM4	N/A	PM4 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
PM5	N/A	The retrieved BRCA1 PM5 rule is PM5_PTC for protein-truncating variants in eligible exons, and c.1534C>T is a missense variant.	cspec vcep_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
PM6	N/A	PM6 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
PP1	Not assessed	No quantitative co-segregation evidence supporting pathogenicity was retrieved for PP1.	cspec
PP2	N/A	PP2 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
PP3	Not met	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. Leu512 lies outside the BRCA1 RING, coiled-coil, and BRCT domains, and SpliceAI is 0.00, which is below the splice threshold of 0.2.	cspec spliceai vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
PP4	Not met	The multifactorial likelihood data retrieved for this variant are against pathogenicity rather than meeting the PP4 thresholds for combined clinical evidence toward pathogenicity.	cspec vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
PP5	N/A	PP5 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
BA1	Not met	BA1 requires a non-founder FAF >0.001. The gnomAD v2.1 grpmax FAF is 8.82e-05, which is below the BA1 threshold.	cspec gnomad_v2
BS1	Met	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.	cspec gnomad_v2
BS2	Not assessed	No unaffected adult or recessive-disease exclusion dataset meeting the BRCA1 BS2 point-based framework was retrieved.	cspec
BS3	Met	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.	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
BS4	Not met	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.	cspec vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
BP1	Met	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.	cspec spliceai vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
BP2	N/A	BP2 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
BP3	N/A	BP3 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
BP4	N/A	For BRCA1 missense variants, BP4 applies inside a clinically important functional domain when BayesDel no-AF <=0.15 and SpliceAI <=0.1. This variant is outside the BRCA1 clinically important domains, so the missense BP4 rule is not the applicable benign in-silico pathway.	cspec vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
BP5	Met	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.	cspec vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
BP6	N/A	BP6 is designated not applicable in the retrieved BRCA1 VCEP specification.	cspec
BP7	Not assessed	No mRNA assay evidence demonstrating a benign transcript profile was retrieved for this missense variant, so BP7 was not applied.	cspec

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