Variant classification summary

NM_007294.3:c.5200T>A

BRCA1 · NP_009225.1:p.(Phe1734Ile) · NM_007294.3

GRCh37: chr17:41209146 A>T · GRCh38: chr17:43057129 A>T

Gene: BRCA1 Transcript: NM_007294.3

Final call

VUS

PS3_Strong PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Phe1734Ile)

gnomAD AF

ClinVar

Likely Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.5200T>A (p.Phe1734Ile; p.F1734I) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity, although the ENIGMA PM2_Supporting rule was not formally established from the available depth-specific evidence.

3

In a calibrated BRCA1 functional study, saturation genome editing showed loss of function similar to pathogenic control variants, and the ENIGMA BRCA1/2 specification assigns PS3 at Strong strength.

4

This missense change is located in the BRCA1 BRCT repeats; REVEL is 0.871, but under the ENIGMA computational rule the observed BayesDel score of 0.242362 and SpliceAI max delta score of 0.00 do not meet PP3 or BP4 thresholds.

Final determination: One Strong pathogenic criterion and one Supporting pathogenic criterion do not meet the ENIGMA Table 3 threshold for Likely Pathogenic or Pathogenic; in the absence of qualifying benign-combination rules, the classification is 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	This variant is a missense substitution, BRCA1 p.(Phe1734Ile), rather than a nonsense, frameshift, canonical +/-1,2 splice, initiation-loss, or exon-level loss-of-function variant. Available evidence does not support a null-variant mechanism for this change, so PVS1 is not applicable.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not assessed	No validated evidence was identified showing that this variant has the same amino acid change as a previously classified pathogenic or likely pathogenic variant, or the same predicted splice effect as a known pathogenic variant. PS1 was therefore not assessed from the available evidence.	cspec
PS2	N/A	De novo evidence is not used for this framework, so PS2 is not applicable.	cspec
PS3	Met	In a calibrated BRCA1 functional study, this variant showed loss of function similar to pathogenic control variants. The ENIGMA BRCA1/2 specification assigns PS3 at Strong strength for BRCA1 c.5200T>A (p.Phe1734Ile).	vcep_specifications_table9_v1_2_2024_11_18 PMID:30209399
PS4	Not assessed	No case-control study or other quantitative enrichment analysis was identified showing that this variant is significantly more common in affected individuals than controls at the ENIGMA PS4 threshold. PS4 was not assessed from the available evidence.	cspec clinvar
PM1	N/A	PM1 is not applicable in this ENIGMA BRCA1/2 framework, even for variants in clinically important domains.	cspec
PM2	Not assessed	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity. However, the ENIGMA PM2_Supporting rule specifically requires absence in gnomAD v2.1 and v3.1 with average read depth at least 25, and the required v3.1/depth-specific evidence was not identified here, so PM2 was not formally applied.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for biallelic BRCA1 disease or a Fanconi anemia context with this variant. PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable in this ENIGMA BRCA1/2 framework.	cspec
PM5	N/A	In this BRCA1 ENIGMA framework, PM5 is repurposed for protein-truncating variants in eligible exons rather than classic same-residue missense logic. Because this variant is a missense substitution and not a protein-truncating variant, PM5 is not applicable.	pm5_candidates cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable in this ENIGMA BRCA1/2 framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable in this ENIGMA BRCA1/2 framework.	cspec
PP3	Not met	This missense variant lies in the BRCA1 BRCT repeats, but the ENIGMA computational threshold for PP3 is not met. REVEL is 0.871, but the governing BRCA1 ENIGMA rule uses BayesDel and SpliceAI; BayesDel is 0.242362, which is below the PP3 threshold of 0.28, and SpliceAI predicts no splice impact with a max delta score of 0.00, below the splice threshold of 0.2.	cspec bayesdel spliceai revel vcep_appendices_v1_2_2024_11_18
PP4	Not met	A BRCA1 clinical-history likelihood ratio was identified for this variant, but it does not reach the ENIGMA PP4 threshold. The observed likelihood ratio is 1.81 from 1 proband, which is below the PP4 Supporting threshold of 2.08.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
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 does not meet the ENIGMA BA1 frequency threshold of filter allele frequency greater than 0.1%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the ENIGMA BS1 frequency thresholds of filter allele frequency greater than 0.002% or greater than 0.01%, depending on strength.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No proband-level data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based framework. BS2 was not assessed.	cspec
BS3	Not met	Available functional evidence does not support normal BRCA1 function for this variant. Instead, the calibrated functional study showed loss of function similar to pathogenic control variants, which supports PS3 rather than BS3.	vcep_specifications_table9_v1_2_2024_11_18 PMID:30209399
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 was not assessed.	cspec
BP1	Not met	This missense variant is within the BRCA1 BRCT repeats, a clinically important functional domain, so it does not meet the ENIGMA BP1 requirement for a variant outside a clinically important domain. SpliceAI also predicts no splice effect, but the domain criterion is not satisfied.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP2	N/A	BP2 is not applicable in this ENIGMA BRCA1/2 framework.	cspec
BP3	N/A	BP3 is not applicable in this ENIGMA BRCA1/2 framework.	cspec
BP4	Not met	This missense variant is within the BRCA1 BRCT repeats, but benign computational evidence is insufficient for BP4. SpliceAI predicts no splice impact with a max delta score of 0.00, meeting the splice portion of the rule, but BayesDel is 0.242362, which is above the BP4 threshold of 0.15. REVEL is also high at 0.871, which does not support a benign computational interpretation.	cspec bayesdel spliceai revel vcep_appendices_v1_2_2024_11_18
BP5	Not met	A BRCA1 clinical-history likelihood ratio was identified for this variant, but it does not meet the ENIGMA BP5 threshold. The observed likelihood ratio is 1.81 from 1 proband, which is above the benign threshold of 0.48 and therefore falls in the neutral zone.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not applicable in this ENIGMA BRCA1/2 framework.	cspec
BP7	N/A	BP7 in this framework applies to silent or qualifying intronic variants, or RNA-only evidence scenarios. This variant is a missense substitution, so BP7 is not applicable.	cspec

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