Variant classification summary

NM_007294.3:c.5140G>T

BRCA1 · NP_009225.1:p.(Val1714Phe) · NM_007294.3

GRCh37: chr17:41215903 C>A · GRCh38: chr17:43063886 C>A

Gene: BRCA1 Transcript: NM_007294.3

Final call

Likely Pathogenic

PS3_Strong PM2_Supporting PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Val1714Phe)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.5140G>T (p.Val1714Phe) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the overall classification is Likely Pathogenic with expert panel review.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

3

In a calibrated BRCA1 functional study, this variant showed complete functional impact consistent with loss of function, and ENIGMA assigns PS3_Strong for this variant.

4

Computational data support a damaging protein effect because the variant is in the BRCT repeats, BayesDel no-AF is 0.482282, and REVEL is 0.812, while SpliceAI predicts no significant splice effect with a max delta score of 0.09.

Final determination: Likely pathogenic based on 1 strong pathogenic criterion with at least 2 supporting pathogenic criteria under ENIGMA Table 3.

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 variant is a missense substitution and does not fall into the BRCA1 null-variant categories used for PVS1. The generic PVS1 scaffold does not place it in a nonsense, frameshift, or canonical ±1,2 splice bucket, and SpliceAI predicts no significant splice effect (max delta score 0.09), so a null mechanism is not supported.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No qualifying previously classified pathogenic or likely pathogenic reference variant with the same amino acid change or the same predicted splicing effect was identified in the reviewed sources, so PS1 was not applied.	cspec
PS2	N/A	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
PS3	Met	In a calibrated functional study, this variant showed loss of function/complete functional impact relative to wild type, and ENIGMA BRCA1 Table 9 assigns PS3 at strong strength for c.5140G>T (p.Val1714Phe). This supports a damaging effect on BRCA1 protein function.	PMID:30209399 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	No case-control study or exact affected-versus-control enrichment data demonstrating significant overrepresentation of this variant were identified, so PS4 was not applied.	cspec clinvar
PM1	N/A	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the ENIGMA BRCA1 specification, absence from controls supports PM2 at supporting strength.	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	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
PM5	N/A	In the ENIGMA BRCA1 specification, PM5 is used for protein-termination variants in exons with established PM5_PTC applicability. This missense variant does not meet that variant-type requirement.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
PP1	Not assessed	No quantitative co-segregation data for this variant were identified, so PP1 was not applied.	cspec vcep_humu_40_1557_s001
PP2	N/A	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
PP3	Met	This missense variant lies within the BRCA1 BRCT repeats, a clinically important functional domain (aa 1650-1857). BayesDel no-AF is 0.482282, which is above the ENIGMA PP3 threshold of 0.28 for damaging protein effect, REVEL is 0.812, and SpliceAI is low at 0.09; together these data support a damaging protein effect rather than a splice-mediated explanation.	cspec vcep_appendices_v1_2_2024_11_18 bayesdel revel spliceai
PP4	Not assessed	No variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant in the reviewed BRCA1 clinical-history resource, so PP4 was not applied.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the ENIGMA BA1 stand-alone threshold of filter allele frequency greater than 0.1%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the ENIGMA BS1 population thresholds of filter allele frequency greater than 0.002% or greater than 0.01%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No point-based evidence from individuals lacking features of BRCA1-related Fanconi anemia was identified, so BS2 was not applied.	cspec
BS3	Not met	Available functional evidence does not show no damaging effect. Instead, calibrated BRCA1 functional data support loss of function for this variant, and ENIGMA assigns PS3_Strong rather than BS3.	PMID:30209399 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 variant was identified, so BS4 was not applied.	cspec vcep_humu_40_1557_s001
BP1	Not met	BP1_Strong applies to missense variants outside the BRCA1 clinically important domains with no predicted splice effect. This variant is p.(Val1714Phe) within the BRCT repeats (aa 1650-1857), so BP1 is not met.	cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
BP3	N/A	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
BP4	Not met	For a BRCA1 missense variant in a clinically important domain, BP4 requires BayesDel no-AF 0.15 or lower and SpliceAI 0.1 or lower. Although SpliceAI is low at 0.09, BayesDel is 0.482282 and REVEL is 0.812, so computational evidence does not support a benign interpretation.	cspec bayesdel revel spliceai
BP5	Not assessed	No variant-level clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant in the reviewed BRCA1 clinical-history resource, so BP5 was not applied.	cspec PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	This criterion is not applicable in the ENIGMA BRCA1 framework for this review.	cspec
BP7	Not met	BP7 in this framework requires qualifying RNA evidence and/or variant-type conditions that are not met here. This is a missense variant within the BRCA1 BRCT functional domain, SpliceAI is low at 0.09, and no RNA assay showing no transcript effect was identified, so BP7 was not applied.	cspec spliceai

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