Variant classification summary

NM_007294.4:c.1233T>G

BRCA1 · NP_009225.1:p.(Asp411Glu) · NM_007294.4

GRCh37: chr17:41246315 A>C · GRCh38: chr17:43094298 A>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Benign

BS1_Strong BS3_Strong BP1_Strong BP6_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Asp411Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.1233T>G (p.Asp411Glu; p.D411E) variant has not been reported in COSMIC and has been reported in ClinVar, including a Benign expert-panel classification from ClinGen ENIGMA.

2

This variant is present in population databases, with gnomAD grpmax FAF values of 0.00024454 in v2.1 and 0.00028752 in v4.1, both above the ENIGMA BS1 threshold of 0.0001 and below the BA1 threshold of 0.001.

3

A calibrated functional study summarized by ENIGMA showed protein function similar to benign control variants for BRCA1 p.Asp411Glu, supporting BS3_Strong.

4

Asp411Glu lies outside the BRCA1 RING, coiled-coil, and BRCT domains, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.07, which is below the 0.1 threshold used for BP1_Strong.

Final determination: Benign is supported because at least two strong benign criteria are met (BS1_Strong and BS3_Strong), which satisfies the ENIGMA Table 3 benign rule.

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 is a missense variant, p.(Asp411Glu), and does not fall into the BRCA1 loss-of-function categories used for PVS1 such as nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or exon-level deletion variants.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified that this variant produces the same protein change or the same predicted splicing effect as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not applied.	cspec clinvar
PS3	Not met	Available functional evidence does not support a damaging effect. ENIGMA Table 9 summarizes this variant as showing protein function similar to benign control variants in a calibrated study, so PS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control study or other prevalence analysis was identified showing this variant is significantly enriched in affected individuals compared with controls, so PS4 was not applied.	cspec clinvar
PM1	N/A	PM1 is not used in this BRCA1 ENIGMA framework.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000425 with grpmax FAF 0.00024454 and in gnomAD v4.1 at AF 0.0000254 with grpmax FAF 0.00028752, so the ENIGMA requirement for absence from controls is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant has been observed with a second BRCA1 variant in a proband with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not applied.	cspec clinvar
PM4	N/A	PM4 is not used in this BRCA1 ENIGMA framework.	cspec
PM5	N/A	In the BRCA1 ENIGMA specification, PM5 is used for protein-terminating variants in eligible exons. This variant is a missense substitution and does not qualify for PM5 under this framework.	cspec vcep_specifications_table4_v1_2_2024_11_18
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not applied.	cspec
PP3	Not met	Available predictive evidence does not support a pathogenic computational call under the ENIGMA BRCA1 rules. SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, which is below the 0.2 PP3 threshold, and this variant is outside the BRCA1 clinically important domains used for missense PP3 application.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BA1	Not met	The population frequency does not reach the ENIGMA BA1 threshold. The highest observed grpmax FAF is 0.00028752 in gnomAD v4.1, which is below the BA1 cutoff of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant exceeds the ENIGMA BS1 threshold for benign population frequency. The grpmax FAF is 0.00024454 in gnomAD v2.1 and 0.00028752 in gnomAD v4.1, both above the BS1 threshold of 0.0001 in a non-founder population.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying evidence was identified showing this variant in enough individuals without features of BRCA1-related Fanconi anemia to reach the ENIGMA BS2 point thresholds, so BS2 was not applied.	cspec clinvar
BS3	Met	A calibrated functional study summarized by ENIGMA showed no damaging effect on protein function for this variant. ENIGMA Table 9 reports BRCA1 c.1233T>G (p.Asp411Glu) as BS3 Strong because one calibrated study found protein function similar to benign control variants.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation data were identified for this variant, so BS4 was not applied.	cspec
BP1	Met	This missense variant is outside the BRCA1 clinically important domains used by ENIGMA and is not predicted to affect splicing. Asp411 lies outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains, and SpliceAI shows a maximum delta score of 0.07, which is below the 0.1 threshold. This meets BP1_Strong.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP2	N/A	BP2 is not used in this BRCA1 ENIGMA framework.	cspec
BP3	N/A	BP3 is not used in this BRCA1 ENIGMA framework.	cspec
BP4	N/A	Under the ENIGMA BRCA1 rules, BP4 for missense variants is used for variants inside clinically important domains with BayesDel <=0.15 and SpliceAI <=0.1. This variant is outside those domains, so BP4 is not the applicable benign computational code here.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP5	Not assessed	No qualifying multifactorial clinical-history likelihood ratio against pathogenicity was identified for this variant. The available BRCA1 clinical-history LR table did not provide a matching variant-level result, so BP5 was not applied.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	Not assessed	No RNA assay evidence was identified showing that this variant has no effect on mRNA splicing, so BP7 was not applied.	cspec spliceai
PP2	N/A	PP2 is not used in this BRCA1 ENIGMA framework.	cspec
PP4	Not assessed	No qualifying multifactorial clinical-history likelihood ratio toward pathogenicity was identified for this variant. The available BRCA1 clinical-history LR table did not provide a matching variant-level result, so PP4 was not applied.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not used in this BRCA1 ENIGMA framework.	cspec
PS2	N/A	PS2 is not used in this BRCA1 ENIGMA framework.	cspec
PM6	N/A	PM6 is not used in this BRCA1 ENIGMA framework.	cspec

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