Variant classification summary

NM_007294.4:c.4481A>G

BRCA1 · NP_009225.1:p.(Glu1494Gly) · NM_007294.4

GRCh37: chr17:41228508 T>C · GRCh38: chr17:43076491 T>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

VUS

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Glu1494Gly)

gnomAD AF

3.0984463150797666e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

All three requested criteria are not applicable under the ENIGMA BRCA1/2 VCEP v1.2 rules: PVS1 is limited to null variants, while PM4 and BP3 are explicitly marked Do not use.

2

The queried variant is NM_007294.4:c.4481A>G, encoding NP_009225.1:p.(Glu1494Gly), and is not a canonical splice-site, in-frame length-change, or repeat-region in-frame variant.

3

For this codon/residue/domain group, PS1 and BP1 are not met because no qualifying pathogenic same-amino-acid comparator was found and SpliceAI max delta 0.122 exceeds the VCEP's 0.1 no-splicing requirement; PM1, PM5, and PP2 are explicitly not used by ENIGMA for this missense variant or framework.

4

The variant is missense (NM_007294.4:c.4481A>G; NP_009225.1:p.(Glu1494Gly), p.E1494G).

5

PP3 is in scope through the VCEP's missense splicing path but is not met because SpliceAI max delta 0.122 is below ≥0.2; the protein-impact path is outside scope because residue 1494 is outside the defined functional domains.

6

BP4 is not applicable because its missense path is restricted to variants inside a defined functional domain.

7

BP7 is not applicable because the variant is missense rather than silent or intronic.

Final determination: Under ENIGMA Table 3, because no pathogenic or benign criterion is met, no listed combination is satisfied and the classification is VUS.

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	Not applicable: c.4481A>G produces p.Glu1494Gly, a missense change rather than the null-variant class required by the ENIGMA PVS1 rule.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1	Not met	Not met: no pathogenic same-amino-acid comparator was found, and the same-residue c.4480G>A comparator is BS3 Strong rather than pathogenic.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS2	N/A	Not applicable: the ENIGMA BRCA1 VCEP explicitly says not to use PS2 because de novo occurrence lacks calibrated predictive value for these relatively common cancers.	cspec
PS3	Not assessed	Not assessed: ENIGMA Table 9 and ST4 contain no c.4481A>G functional-assay entry or calibrated damaging-effect assignment.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PS4	Not assessed	Not assessed: no variant-specific case-control p-value, odds ratio, or confidence interval is available to test the PS4 requirements.	cspec
PM1	N/A	Not applicable: ENIGMA says PM1 is not used, and residue 1494 lies outside the listed RING, coiled-coil, and BRCT domains.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	Not met	Not met: the variant was present in gnomAD v2.1 non-cancer exomes at AF 4.22494e-06, so it was not absent from controls.	cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2
PM3	Not assessed	Not assessed: no documented same-gene pathogenic/likely pathogenic co-occurrence, phase, or BRCA1-related Fanconi Anemia phenotype was available to assign the VCEP's 1-, 2-, or ≥4-point PM3 threshold.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	Not applicable: the VCEP says Do not use PM4, and c.4481A>G is a missense substitution rather than an in-frame length change or stop-loss variant.	cspec vcep_specifications_v1_2_2024_11_18
PM5	N/A	Not applicable: ENIGMA does not use missense PM5, and this p.Glu1494Gly missense variant is not a PVS1 protein-termination-codon variant.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	Not applicable: the ENIGMA BRCA1 VCEP explicitly says not to use PM6 because de novo occurrence lacks calibrated predictive value for these relatively common cancers.	cspec
PP1	Not assessed	Not assessed: no quantitative affected-family co-segregation data or Bayes-score likelihood ratio was available to compare with the PP1 threshold of LR ≥2.08:1.	cspec
PP2	N/A	Not applicable: ENIGMA explicitly does not use PP2 for BRCA1 because benign missense variants are frequent.	cspec vcep_specifications_v1_2_2024_11_18
PP3	Not met	Not met: SpliceAI max delta 0.122 is below the ENIGMA PP3 splicing threshold of ≥0.2 for missense variants.	cspec spliceai bayesdel
PP4	N/A	Not applicable: Li et al. reports LR 1.241736334803197, which is within the VCEP's 1.00 to <2.08 non-informative PP4 interval.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	Not applicable: the ENIGMA VCEP explicitly states “Do not use” for PP5.	cspec
BA1	Not assessed	Not assessed: gnomAD v2.1 non-cancer AF was 4.22494e-06, but the VCEP requires FAF >0.001 and FAF was unavailable.	cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS1	Not assessed	Not assessed: gnomAD v2.1 non-cancer AF was 4.22494e-06, but BS1 requires FAF thresholds and FAF was unavailable.	cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS2	Not assessed	Not assessed: no qualifying trans co-occurrence, homozygote, or age/follow-up observation was available for the BS2 point system.	cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS3	Not assessed	Not assessed: ENIGMA Table 9 and ST4 contain no c.4481A>G functional-assay entry or calibrated no-damaging-effect assignment.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS4	Not assessed	Not assessed: no quantitative non-segregation data or Bayes-score likelihood ratio was available to compare with the BS4 supporting threshold of LR ≤0.48:1.	cspec
BP1	Not met	Not met: residue 1494 is outside approved domains, but SpliceAI max delta 0.122 exceeds the BP1_Strong threshold of <=0.1.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2	N/A	Not applicable: ENIGMA explicitly says BP2 is not used and limits it to the BS2 context.	cspec vcep_specifications_v1_2_2024_11_18
BP3	N/A	Not applicable: the VCEP says Do not use BP3, and c.4481A>G is a missense substitution rather than an in-frame repeat-region insertion or deletion.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4	N/A	Not applicable: p.Glu1494 lies outside ENIGMA's defined functional domains, so BP4's missense path does not cover this variant.	cspec spliceai bayesdel
BP5	N/A	Not applicable: LR 1.241736334803197 is not ≤0.48 and lies above the VCEP's informative BP5 range.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	Not applicable: the ENIGMA VCEP explicitly states “Do not use” for BP6.	cspec
BP7	N/A	Not applicable: BP7 covers silent or intronic variants, whereas c.4481A>G is a missense substitution producing p.Glu1494Gly.	cspec spliceai

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