Variant classification summary

NM_007294.4:c.4530G>A

BRCA1 · NP_009225.1:p.(Met1510Ile) · NM_007294.4

GRCh37: chr17:41226493 C>T · GRCh38: chr17:43074476 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

BP1_Strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Met1510Ile)

gnomAD AF

6.19528018774177e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.4530G>A (p.Met1510Ile) variant has been reported in ClinVar as a variant of uncertain significance with three clinical laboratory submissions.

2

This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 1/1,614,132 alleles (AF 6.20e-07), indicating that it is very rare but not absent from population databases.

3

No variant-specific calibrated functional assay result for c.4530G>A (p.Met1510Ile) was identified in the reviewed ENIGMA BRCA1 functional tables, so PS3 and BS3 were not applied.

4

Computational evidence supports a benign direction under the BRCA1 ENIGMA rules because this missense change lies outside the BRCA1 clinically important domains and SpliceAI predicts no significant splice effect (max delta score 0.03), meeting BP1_Strong; BayesDel no-AF is -0.119 and does not meet the PP3 threshold, and REVEL is 0.534.

5

The BRCA1 clinical-history likelihood ratio for this variant is 1.90 in one proband, which falls between the ENIGMA BP5 threshold of 0.48 and the PP4 threshold of 2.08, so neither PP4 nor BP5 was applied.

Final determination: BP1_Strong alone does not meet ENIGMA Table 3 thresholds for likely benign or benign classification; this variant is therefore classified as of 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	BRCA1 loss of function is an established disease mechanism, but this variant is a missense substitution, not a nonsense, frameshift, initiation-loss, or canonical ±1,2 splice variant. Available data therefore do not place this variant into the ENIGMA BRCA1 PVS1 framework.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No same-amino-acid pathogenic comparator was identified from the available evidence, so PS1 was not applied.	cspec clinvar
PS2	N/A	De novo evidence is not used in this ENIGMA BRCA1 framework.	cspec
PS3	Not assessed	No variant-specific calibrated functional study result supporting a damaging effect was identified in the reviewed ENIGMA BRCA1 functional tables, so PS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	No case-control analysis or quantified enrichment of this variant in affected individuals versus controls was identified, so PS4 was not applied.	cspec clinvar
PM1	N/A	PM1 is not used in this ENIGMA BRCA1 framework.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at 1/1,614,132 alleles (AF 6.20e-07; highest subpopulation AF 8.47e-07 in European non-Finnish). Because the variant is not absent from population controls, PM2 was not applied.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed with another BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not applied.	cspec
PM4	N/A	PM4 is not used in this ENIGMA BRCA1 framework.	cspec
PM5	N/A	In this ENIGMA BRCA1 framework, PM5 is repurposed for protein-terminating variants in exons with prior proven pathogenic truncating variants. This variant is a missense substitution, so PM5 does not apply.	cspec pm5_candidates
PM6	N/A	De novo evidence is not used in this ENIGMA BRCA1 framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	PP2 is not used in this ENIGMA BRCA1 framework.	cspec
PP3	Not met	This missense variant lies outside the BRCA1 clinically important domains used for PP3, SpliceAI predicts no significant splice effect (max delta score 0.03; PP3 splice threshold ≥0.2), and BayesDel no-AF is -0.119, below the BRCA1 pathogenic threshold of ≥0.28. REVEL is 0.534, but the BRCA1 ENIGMA computational rule uses BayesDel and SpliceAI, so PP3 was not met.	cspec spliceai bayesdel revel
PP4	Not met	The BRCA1 clinical-history likelihood ratio for this variant is 1.90 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08. This value falls in the neutral zone, so PP4 was not applied.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not used in this ENIGMA BRCA1 framework.	cspec
BA1	Not met	The highest observed population frequency is 8.47e-07 in gnomAD v4.1, which is far below the BRCA1 ENIGMA BA1 threshold of FAF >0.001. BA1 was not met.	cspec gnomad_v4
BS1	Not met	The highest observed population frequency is 8.47e-07 in gnomAD v4.1, which is below the BRCA1 ENIGMA BS1 thresholds of >2.0e-05 for BS1_Supporting and >1.0e-04 for BS1. BS1 was not met.	cspec gnomad_v4
BS2	Not assessed	No qualifying observations in individuals without Fanconi anemia features were identified, so BS2 was not applied.	cspec
BS3	Not assessed	No variant-specific calibrated functional study result showing no damaging effect was identified in the reviewed ENIGMA BRCA1 functional tables, so BS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not applied.	cspec
BP1	Met	This is a missense variant outside the BRCA1 clinically important domains used by ENIGMA, and SpliceAI predicts no significant splice impact (max delta score 0.03, below the ≤0.1 threshold). This supports BP1_Strong.	cspec spliceai
BP2	N/A	BP2 is not used in this ENIGMA BRCA1 framework.	cspec
BP3	N/A	BP3 is not used in this ENIGMA BRCA1 framework.	cspec
BP4	N/A	For BRCA1 missense variants, BP4 is reserved for variants inside a clinically important functional domain with no predicted protein or splice impact. This variant lies outside those domains, so BP4 does not apply; the framework instead captures this pattern with BP1.	cspec spliceai bayesdel
BP5	Not met	The BRCA1 clinical-history likelihood ratio for this variant is 1.90 in 1 proband, which is above the ENIGMA BP5 threshold of 0.48. Because the value falls in the neutral zone, BP5 was not applied.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in this ENIGMA BRCA1 framework.	cspec
BP7	Not assessed	BP7 in this framework requires RNA evidence showing no damaging transcript effect for a qualifying variant type. No variant-specific RNA study was identified for this missense change, so BP7 was not applied.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18

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