Variant classification summary

NM_007294.4:c.2155A>G

BRCA1 · NP_009225.1:p.(Lys719Glu) · NM_007294.4

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

Gene: BRCA1 Transcript: NM_007294.4

Final call

Benign

BS1_Strong BP1_Strong BP5_Strong BP6_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Lys719Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.2155A>G (p.Lys719Glu; p.K719E) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1 and BRCA2 expert panel classified it as benign.

2

This variant is present in gnomAD v2.1 and v4.1, with grpmax filter allele frequencies of 0.00062195 and 0.00068503, respectively, both above the ENIGMA BS1 strong threshold of 0.0001 and below the BA1 threshold of 0.001.

3

A BRCA1 clinical-history likelihood ratio of 0.0137 from 10 probands is below the ENIGMA BP5_Strong threshold of 0.05, supporting evidence against pathogenicity.

4

No variant-specific damaging or benign functional result for c.2155A>G (p.Lys719Glu) was identified in the reviewed ENIGMA functional assay resources, so PS3 and BS3 were not assessed.

5

The p.Lys719Glu change lies outside the BRCA1 RING, coiled-coil, and BRCT domains defined by ENIGMA, and SpliceAI predicts no splice impact with a maximum delta score of 0.00, supporting BP1_Strong and not supporting PP3.

Final determination: Benign classification is met because at least two strong benign criteria are present (BS1_Strong, BP1_Strong, and BP5_Strong), which satisfies the ENIGMA Table 3 benign combination 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	Not met	This missense variant does not fall into the BRCA1 loss-of-function categories used for PVS1. It is not a nonsense, frameshift, initiation-codon, canonical ±1,2 splice-site, or exon-level deletion/duplication variant, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously classified pathogenic or likely pathogenic variant with the same established amino acid or splice effect was identified in the reviewed evidence, so PS1 was not assessed.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	PS2 is not applied in the BRCA1 ENIGMA specification.	cspec
PS3	Not assessed	No variant-specific damaging functional result for c.2155A>G (p.Lys719Glu) was identified in the reviewed ENIGMA functional resources, so PS3 was not assessed.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	No case-control study or quantitative prevalence analysis showing a significant enrichment of this variant in affected individuals was identified, so PS4 was not assessed.	cspec
PM1	Not met	This variant is outside the BRCA1 clinically important functional domains defined by ENIGMA, and no hotspot evidence was identified. The affected residue is Lys719, which is outside the RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857), so PM1 is not met.	cspec vcep_appendices_v1_2_2024_11_18 hotspots
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000708 (20/282394 alleles) and in gnomAD v4.1 at AF 0.0000415 (67/1614060 alleles), so the ENIGMA PM2 absence threshold is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA1 variant in an individual with BRCA1-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applied in the BRCA1 ENIGMA specification.	cspec
PM5	N/A	Under the BRCA1 ENIGMA specification, PM5 is used for protein-truncating variants in exons where a different proven pathogenic truncating variant has already been observed. This variant is missense, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	PM6 is not applied in the BRCA1 ENIGMA specification.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applied in the BRCA1 ENIGMA specification.	cspec
PP3	Not met	Available predictive evidence does not meet the ENIGMA PP3 thresholds. The variant lies outside the BRCA1 clinically important domains used for missense PP3, and SpliceAI shows no predicted splice effect with a maximum delta score of 0.00, which is below the PP3 splice threshold of 0.20.	cspec spliceai vcep_appendices_v1_2_2024_11_18
PP4	Not met	The available BRCA1 clinical-history likelihood ratio is 0.0137 from 10 probands, which is well below the PP4 pathogenic threshold of 2.08. This evidence does not support PP4.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not applied in the BRCA1 ENIGMA specification.	cspec
BA1	Not met	The filter allele frequency does not reach the ENIGMA BA1 threshold. The highest observed grpmax FAF is 0.00062195 in gnomAD v2.1 and 0.00068503 in gnomAD v4.1, both below the BA1 cutoff of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant exceeds the ENIGMA BS1 strong threshold for population frequency. The highest observed grpmax FAF is 0.00062195 in gnomAD v2.1 and 0.00068503 in gnomAD v4.1, both above the BS1 strong cutoff of 0.0001 and below the BA1 cutoff of 0.001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying observations in unaffected individuals were identified for the ENIGMA BRCA1 BS2 points-based framework, so BS2 was not assessed.	cspec
BS3	Not assessed	No variant-specific benign functional result for c.2155A>G (p.Lys719Glu) was identified in the reviewed ENIGMA functional resources, so BS3 was not assessed.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed.	cspec
BP1	Met	This missense variant is outside the BRCA1 clinically important functional domains used by ENIGMA, and SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the BP1 splice threshold of 0.10. These findings meet BP1_Strong.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP2	N/A	BP2 is not applied in the BRCA1 ENIGMA specification.	cspec
BP3	N/A	BP3 is not applied in the BRCA1 ENIGMA specification.	cspec
BP4	N/A	This missense variant is outside the BRCA1 domain and variant classes for which ENIGMA applies BP4. Under the BRCA1 specification, missense variants outside clinically important domains are evaluated with BP1 rather than BP4 when splicing is not predicted to be affected.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP5	Met	The BRCA1 clinical-history likelihood ratio for this variant is 0.0137 from 10 probands, which is below the BP5_Strong threshold of 0.05. This provides strong evidence against pathogenicity under the ENIGMA multifactorial clinical-data framework.	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 qualifying RNA study showing no damaging effect on transcript processing was identified for this missense variant, so BP7 was not assessed.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18

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.