Variant classification summary

NM_007294.3:c.4211T>G

BRCA1 · NP_009225.1:p.(Leu1404Arg) · NM_007294.3

GRCh37: chr17:41234567 A>C · GRCh38: chr17:43082550 A>C

Gene: BRCA1 Transcript: NM_007294.3

Final call

BP4_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Leu1404Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.4211T>G (p.Leu1404Arg) variant has been reported in ClinVar, including an ENIGMA expert-panel classification of uncertain significance.

2

This variant is very rare in population databases, with 1 of 251348 alleles in gnomAD v2.1 (AF 3.97855e-06; highest observed East Asian AF 5.43892e-05) and no observation in gnomAD v4.1.

3

In silico evidence supports a benign computational interpretation under the ENIGMA BRCA1 framework because the variant is in the coiled-coil domain, BayesDel no-AF is 0.094842 (BP4 threshold ≤0.15), and SpliceAI max delta score is 0.02 (BP4 threshold ≤0.1); REVEL is 0.331 but does not alter the VCEP rule assignment.

Final determination: BP4_Supporting alone does not meet the ENIGMA Table 3 threshold for Likely Benign or Benign classification; therefore the variant is classified as Uncertain Significance.

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	This variant is a missense substitution, p.(Leu1404Arg), and does not fall into the BRCA1 loss-of-function categories used for PVS1 such as nonsense, frameshift, or canonical ±1,2 splice variants.	cspec pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	No previously classified variant causing the same amino acid change was identified in the reviewed BRCA1 materials, so PS1 could not be established from the available evidence.	cspec
PS2	N/A	This BRCA1 specification marks PS2 as not applicable for this framework.	cspec
PS3	Not assessed	No variant-specific damaging functional result for c.4211T>G (p.Leu1404Arg) was identified in the reviewed ENIGMA BRCA1 curated functional tables, so PS3 is not established from the available evidence.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control evidence showing significant enrichment in affected individuals at the ENIGMA BRCA1 PS4 threshold was identified.	cspec clinvar
PM1	N/A	This BRCA1 specification marks PM1 as not applicable in this framework.	cspec
PM2	Not met	This variant is not absent from controls because it is present once in gnomAD v2.1 (1/251348 alleles; AF 3.97855e-06; highest observed East Asian AF 5.43892e-05), even though it is absent from gnomAD v4.1. The ENIGMA BRCA1 PM2 rule requires absence from controls, so PM2 is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant occurred with a second BRCA1 variant in a person with BRCA1-related Fanconi anemia, so PM3 could not be assessed.	cspec
PM4	N/A	This BRCA1 specification marks PM4 as not applicable in this framework.	cspec
PM5	N/A	In this BRCA1 specification, PM5 is used for protein-truncating variants with a premature termination codon in eligible exons. This variant is missense, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This BRCA1 specification marks PM6 as not applicable for this framework.	cspec
PP1	Not assessed	No quantitative co-segregation evidence for this exact variant was identified, so PP1 could not be assessed.	cspec vcep_humu_40_1557_s001
PP2	N/A	This BRCA1 specification marks PP2 as not applicable in this framework.	cspec
PP3	Not met	Available computational evidence does not support PP3 under the ENIGMA BRCA1 rule. BayesDel no-AF is 0.094842, which is below the PP3 threshold of ≥0.28, and SpliceAI max delta score is 0.02, which is below the splice threshold of ≥0.2. REVEL is 0.331, but ENIGMA BRCA1 uses BayesDel and SpliceAI for this rule.	cspec bayesdel spliceai revel
PP4	Not assessed	No variant-specific clinical-history likelihood ratio was identified for this exact BRCA1 variant in the reviewed clinical-history resource, so PP4 could not be assigned.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	This BRCA1 specification marks PP5 as not applicable in this framework.	cspec
BA1	Not met	Population data do not meet BA1. The variant was seen once in gnomAD v2.1 and was absent from gnomAD v4.1, and no non-founder population frequency above the BRCA1 BA1 threshold was identified.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Population data do not meet BS1. The variant is very rare in gnomAD v2.1 and absent from gnomAD v4.1, and no non-founder population filter allele frequency above the BRCA1 BS1 thresholds was identified.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in individuals meeting the BRCA1 BS2 framework for absence of Fanconi anemia features, so BS2 could not be assessed.	cspec
BS3	Not assessed	No variant-specific benign functional result for c.4211T>G (p.Leu1404Arg) was identified in the reviewed ENIGMA BRCA1 curated functional tables, so BS3 is not established from the available evidence.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation evidence for this exact variant was identified, so BS4 could not be assessed.	cspec vcep_humu_40_1557_s001
BP1	Not met	This missense variant is in the BRCA1 coiled-coil domain (aa 1391-1424), which is a clinically important functional domain in the ENIGMA BRCA1 specification, so it does not meet BP1_Strong for variants outside such domains.	cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	This BRCA1 specification marks BP2 as not applicable in this framework.	cspec
BP3	N/A	This BRCA1 specification marks BP3 as not applicable in this framework.	cspec
BP4	Met	This missense variant lies in the BRCA1 coiled-coil domain (aa 1391-1424). BayesDel no-AF is 0.094842, which is below the BRCA1 BP4 threshold of ≤0.15, and SpliceAI max delta score is 0.02, which is below the ≤0.1 splice threshold. These findings support BP4_Supporting under the ENIGMA BRCA1 rule. REVEL is 0.331 and does not change the VCEP rule assignment.	cspec vcep_appendices_v1_2_2024_11_18 bayesdel spliceai revel
BP5	Not assessed	No variant-specific clinical-history likelihood ratio in the benign direction was identified for this exact BRCA1 variant in the reviewed clinical-history resource, so BP5 could not be assigned.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	This BRCA1 specification marks BP6 as not applicable in this framework.	cspec
BP7	Not assessed	No RNA study showing no transcript effect was identified for this variant. SpliceAI predicts little splice effect (max delta score 0.02), but BP7 in this framework requires the variant-type and study conditions described by the BRCA1 specification, so BP7 is not established from the available evidence.	cspec spliceai

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