Variant classification summary

NM_007294.4:c.4450T>G

BRCA1 · NP_009225.1:p.(Ser1484Ala) · NM_007294.4

GRCh37: chr17:41228539 A>C · GRCh38: chr17:43076522 A>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

PM2 supporting BP1 strong benign

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Ser1484Ala)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.4450T>G (p.Ser1484Ala) is a missense variant in BRCA1 exon 13 located at amino acid position 1484, outside all ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857). SpliceAI predicts no splicing impact (max delta 0.03).

2

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.

3

The variant meets ENIGMA BP1_Strong: missense variant outside a clinically important functional domain with no predicted splicing impact (SpliceAI max delta 0.03 ≤0.1).

4

This variant is not listed in ENIGMA Table9 (curated functional assays) or ST4 (functional assay results) for either PS3 or BS3. The related variant c.4450T>A (p.Ser1484Thr) has BS3_Strong with 'No functional impact,' but this is a different amino acid substitution and does not constitute direct evidence for p.Ser1484Ala.

5

No case-control, segregation, or clinical-history likelihood ratio data were identified for this specific variant. It is not listed in the Li et al. 2020 (PMID:31853058) clinical-history LR table; c.4450T>A is listed with neutral LR=1.066.

6

In ClinVar, this variant is classified as Uncertain Significance by three clinical laboratories (ClinVar ID 630099). No expert panel classification is available.

7

Under the ENIGMA Table 3 all_of combination rules, one Strong Benign criterion (BP1_Strong) with no qualifying Supporting Benign or Moderate Benign criterion does not meet the Likely Benign threshold (requires Strong Benign + Supporting Benign or Strong Benign + Moderate Benign). The conflicting PM2_Supporting (pathogenic direction) further precludes a benign or likely benign classification. The variant remains a Variant of Uncertain Significance.

Final determination: Conflicting evidence resolved by ENIGMA point system: PM2_Supporting (+1) + BP1_Strong (-4) = -3 total, mapping to Likely Benign (-6 to -2).

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	PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, exon deletion) per ENIGMA BRCA1 specification v1.2. This variant is a missense substitution (c.4450T>G, p.Ser1484Ala) and does not qualify.	cspec pvs1_variant_assessment
PS1	Not met	No previously classified pathogenic missense variant with the same amino acid change (p.Ser1484Ala) exists in the ENIGMA reference set. The only variant at this residue in ENIGMA tables is c.4450T>A (p.Ser1484Thr), which has BS3 (benign) in Table9 and 'No functional impact' in ST4. PS1 requires a pathogenic or likely pathogenic comparator at the same residue with the same predicted effect; none is available.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 spliceai
PS2	N/A	PS2 (de novo) is listed as Not Applicable in the ENIGMA BRCA1 specification v1.2. De novo assessment for BRCA1 is not part of the ENIGMA framework.	cspec
PS3	Not met	This variant is not listed in ENIGMA Table9 (curated functional assay results) for PS3. It is not present in ST4 (full functional assay results dataset). Exploratory search found no published functional studies demonstrating a damaging effect for p.Ser1484Ala specifically. The related variant c.4450T>A (p.Ser1484Thr) has BS3_Strong ('No functional impact'), but this pertains to a different amino acid substitution and does not constitute evidence for this variant.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not met	No case-control study demonstrates significantly increased prevalence of c.4450T>G in affected individuals versus controls. The variant is absent from gnomAD, making population-based odds ratio calculation infeasible. ENIGMA requires OR ≥4 (lower CI excludes 2.0) with p≤0.05 from a study of independent probands; no such study was identified.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 is not defined in the ENIGMA BRCA1 specification v1.2 criteria set. This criterion is not used in the ENIGMA framework.	cspec
PM1	N/A	PM1 is listed as Not Applicable in the ENIGMA BRCA1 specification v1.2. ENIGMA captures domain-level evidence through other criteria (PP3/BP4 for variants inside functional domains, BP1 for variants outside).	cspec
PM2	Met	This variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer), meeting ENIGMA PM2_Supporting. The variant is absent from all outbred population controls in these databases.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA repurposes PM5 for protein termination codon (PTC) variants in exons where a different proven pathogenic PTC variant has been observed. This is a missense variant (p.Ser1484Ala), not a PTC. PM5 classic same-residue missense comparison is not used under ENIGMA.	cspec pm5_candidates
PM6	N/A	PM6 (de novo) is listed as Not Applicable in the ENIGMA BRCA1 specification v1.2.	cspec
PP1	Not met	No co-segregation data are available for this variant. No published pedigrees or segregation analyses document co-segregation of c.4450T>G with disease in multiple affected family members. ENIGMA requires a quantitative co-segregation analysis with LR ≥2.08 for PP1.	clinvar
PP2	N/A	PP2 is listed as Not Applicable in the ENIGMA BRCA1 specification v1.2.	cspec
PP3	Not met	ENIGMA PP3 for missense variants applies only to variants inside a clinically important functional domain with BayesDel ≥0.28. The variant p.Ser1484Ala is at amino acid position 1484, which lies outside all ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel score is -0.315 (below the 0.28 threshold). SpliceAI max delta is 0.03 (below the 0.2 splicing-based PP3 threshold). Neither path to PP3 is satisfied.	cspec bayesdel spliceai revel
PP4	Not met	This variant (c.4450T>G) is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. The related variant c.4450T>A (p.Ser1484Thr) is present with LR=1.066 (N_Probands=1), which falls in the neutral zone (>0.48 and <2.08) and would not qualify for PP4 or BP5. No multifactorial likelihood data supporting pathogenicity were identified for c.4450T>G in any ENIGMA resource.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001
PP5	N/A	PP5 is listed as Not Applicable in the ENIGMA BRCA1 specification v1.2. Reputable source classification is not used as a standalone criterion in the ENIGMA framework.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1. ENIGMA BA1 requires filter allele frequency (FAF) >0.1% (FAF >0.001) in gnomAD non-cancer, non-founder populations. Absence does not meet this threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1. ENIGMA BS1_Strong requires FAF >0.01% (>0.0001) and BS1_Supporting requires FAF >0.002% (>0.00002). Absence from population databases does not satisfy either threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence was identified documenting observation of this variant in healthy adults without features of Fanconi Anemia (FA) in sufficient numbers to meet ENIGMA BS2 point thresholds (≥1 point for BS2_Supporting, ≥2 for Moderate, ≥4 for Strong). Absent from gnomAD population databases, which precludes inference from population homozygote counts.	gnomad_v2 gnomad_v4
BS3	Not met	This variant (c.4450T>G, p.Ser1484Ala) is not listed in ENIGMA Table9 for BS3 and is not present in ST4 (full functional assay dataset). The related variant c.4450T>A (p.Ser1484Thr) has BS3_Strong with 'No functional impact' in Table9 and ST4, but this is a different amino acid substitution (Thr vs Ala) and does not constitute evidence for p.Ser1484Ala. No published functional studies demonstrate a benign effect for this specific variant.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not met	No lack-of-segregation data are available for this variant. No published pedigrees document non-segregation of c.4450T>G with disease in affected family members. ENIGMA requires quantitative co-segregation analysis with LR ≤0.48 for BS4_Supporting.	clinvar
BP1	Met	This missense variant (p.Ser1484Ala) is located at amino acid position 1484, which lies outside all ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857). SpliceAI predicts no splicing impact (max delta score = 0.03, ≤0.1). This meets ENIGMA BP1_Strong per the specification: missense variant outside a clinically important functional domain AND no splicing predicted.	cspec spliceai
BP2	N/A	BP2 is listed as Not Applicable in the ENIGMA BRCA1 specification v1.2.	cspec
BP4	Not met	ENIGMA BP4 for missense variants applies only to variants inside a clinically important functional domain with BayesDel ≤0.15 AND SpliceAI ≤0.1. This variant is at aa 1484, outside all ENIGMA functional domains (RING 2-101, coiled-coil 1391-1424, BRCT 1650-1857). Under the ENIGMA Figure 1A flowchart, missense variants outside functional domains are routed through BP1 rather than BP4. BP4 does not apply here.	cspec bayesdel spliceai
BP5	Not met	This variant (c.4450T>G) is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. The related variant c.4450T>A (p.Ser1484Thr) has LR=1.066 (N_Probands=1), which falls in the neutral zone and would not qualify for BP5. No multifactorial likelihood data supporting benignity were identified for c.4450T>G.	vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001
BP6	N/A	BP6 is listed as Not Applicable in the ENIGMA BRCA1 specification v1.2.	cspec
BP7	Not met	ENIGMA BP7_Strong (RNA) requires well-established mRNA assay data showing no splicing aberration. This variant has not been assessed in any mRNA transcript analysis; it is absent from ENIGMA ST3 (splicing references). SpliceAI alone (max delta 0.03) is predictive but does not substitute for experimental mRNA evidence required for BP7. BP7_Supporting applies only to silent or intronic variants and is not applicable to this missense variant.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18

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