Variant classification summary

NM_007294.3:c.2155A>G

BRCA1 · NP_009225.1:p.(Lys719Glu) · NM_007294.3

GRCh37: chr17:41245393 T>C · GRCh38: chr17:43093376 T>C

Gene: BRCA1 Transcript: NM_007294.3

Final call

Benign

BS1_Strong BP1_Strong BP5_Strong BP6_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Lys719Glu)

gnomAD AF

4.151022886385884e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 NM_007294.3:c.2155A>G (NP_009225.1:p.(Lys719Glu), NP_009225.1:p.(K719E)) variant has not been observed in COSMIC and has been reported in ClinVar with a current expert-panel Benign classification, although older laboratory submissions include uncertain significance and likely benign assertions.

2

This variant is present in population databases, including gnomAD v2.1 and v4.1, with grpmax FAF values of 0.00062195 and 0.00068503, respectively, which are above the ENIGMA BS1 threshold of 0.0001 but below the BA1 threshold of 0.001.

3

Multifactorial clinical-history evidence is in the benign direction, with a BRCA1 clinical-history likelihood ratio of 0.0137 from 10 probands, meeting BP5_Strong and arguing against pathogenicity.

4

In silico evidence does not support a damaging effect in the ENIGMA BRCA1 framework: SpliceAI predicts no splice impact (max delta score 0.00), BayesDel is -0.216062, and the missense change lies outside the BRCA1 domains used for PP3/BP4, supporting BP1_Strong rather than PP3.

Final determination: Benign classification is supported by multiple benign criteria, including at least two strong benign criteria under the ENIGMA BRCA1/BRCA2 Table 3 combination rules.

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 missense variant does not fall within the BRCA1 ENIGMA loss-of-function categories for PVS1. It is not a nonsense, frameshift, canonical ±1/2 splice, initiation-codon, or exon-level deletion variant, and SpliceAI does not predict an abnormal splice effect (max delta score 0.00).	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	Available evidence did not identify a separate pathogenic nucleotide change producing the same amino acid substitution. This amino acid change is generated by the observed codon-level substitution itself, so PS1 is not supported here.	cspec clinvar
PS2	N/A	No de novo framework is used for BRCA1 in this ENIGMA specification.	cspec
PS3	Not assessed	No variant-specific calibrated functional study showing a damaging effect was identified in the available evidence, so PS3 cannot be applied at this time.	cspec oncokb vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control or enrichment data showing this variant is significantly more common in affected individuals than in controls were identified, so PS4 was not applied.	cspec clinvar
PM1	N/A	PM1 is not used in this BRCA1 ENIGMA framework for this variant context.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000708 with African/African American AF 0.000803 and grpmax FAF 0.00062195, and in gnomAD v4.1 at AF 0.0000415 with African/African American AF 0.000853 and grpmax FAF 0.00068503; therefore 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 was observed with a second BRCA1 pathogenic variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not applied.	cspec
PM4	N/A	PM4 is not applicable because this is not a protein length-changing in-frame variant or stop-loss variant, and the ENIGMA BRCA1 specification marks PM4 as not applicable.	cspec
PM5	N/A	In this BRCA1 ENIGMA framework, PM5 is repurposed for truncating or protein-termination-codon logic and not for classic same-residue missense comparison. Because this variant is a missense substitution, PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	No de novo framework is used for BRCA1 in this ENIGMA specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec clinvar
PP2	N/A	PP2 is not used in this BRCA1 ENIGMA framework.	cspec
PP3	Not met	Computational evidence does not meet the BRCA1 ENIGMA PP3 rule. The variant is outside the specified clinically important BRCA1 domains, BayesDel is -0.216062 which is below the PP3 threshold of 0.28, SpliceAI shows no predicted splice effect with max delta score 0.00, and REVEL is 0.404 but REVEL is not the governing ENIGMA threshold for BRCA1 PP3.	cspec bayesdel spliceai revel
PP4	Not met	Available multifactorial clinical-history evidence is in the benign direction rather than the pathogenic direction. The BRCA1 clinical-history likelihood ratio is 0.0137 from 10 probands, which is well below the PP4 threshold of 2.08 and therefore does not support PP4.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not used in this BRCA1 ENIGMA framework.	cspec
BA1	Not met	The population frequency does not reach the ENIGMA BA1 threshold. The highest observed grpmax FAF is 0.00068503 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 0.00062195 in gnomAD v2.1 and 0.00068503 in gnomAD v4.1, both above the BS1 cutoff of 0.0001 and below the BA1 cutoff of 0.001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No proband-level evidence was identified to score absence of BRCA1-related Fanconi anemia features, so BS2 was not applied.	cspec
BS3	Not assessed	No variant-specific calibrated functional study showing no damaging effect was identified in the available evidence, so BS3 cannot be applied at this time.	cspec oncokb vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not applied.	cspec clinvar
BP1	Met	This is a missense variant outside the BRCA1 clinically important functional domains used by the ENIGMA framework, and SpliceAI predicts no splice effect with a max delta score of 0.00. These findings meet BP1_Strong for a missense change outside a critical domain without predicted splicing impact.	cspec spliceai
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	BP4 is not the appropriate benign computational rule for this missense variant because the BRCA1 ENIGMA specification restricts BP4 missense use to variants inside defined clinically important domains with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. This variant is outside those domains, so benign computational support is captured by BP1 instead.	cspec bayesdel spliceai
BP5	Met	Available multifactorial clinical-history evidence supports a benign direction. The BRCA1 clinical-history likelihood ratio is 0.0137 from 10 probands, which is below the BP5_Strong threshold of 0.05 and above the Very Strong threshold of 0.00285, so BP5_Strong is met.	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 study demonstrating a normal transcript profile for this variant was identified, so BP7 was not applied.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.