NM_007294.4:c.2182A>T

BRCA1 · NP_009225.1:p.(Arg728Ter) · NM_007294.4

GRCh37: chr17:41245366 T>A · GRCh38: chr17:43093349 T>A

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1 very strong PM5 strong PM2 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Arg728Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_007294.4:c.2182A>T (p.Arg728Ter) is a nonsense variant in BRCA1 exon 10 (legacy exon 11), predicted to undergo nonsense-mediated decay (>1900 nt upstream of the terminal exon junction).

Per ENIGMA Specification Table 4, BRCA1 exon 10 PTC variants are assigned PVS1 (Very Strong) weight. Loss of function is an established disease mechanism for BRCA1.

ENIGMA Specification Table 4 assigns PM5_Strong (PTC) for nonsense variants in BRCA1 exon 10, where multiple proven pathogenic PTC variants have been observed. This is supported by ≥4 evidence points across functional assay, case-control, personal/family history, and CIMBA data (Supplementary Table 1).

The variant is absent from gnomAD v2.1 (non-cancer, exome only), gnomAD v4.1 (non-cancer), and gnomAD-Canada v1.0, meeting ENIGMA PM2_Supporting.

ENIGMA point-based combining rules (Table 3): PVS1 Very Strong (8 points) + PM5 Strong (4 points) + PM2 Supporting (1 point) = 13 points, meeting the Pathogenic threshold (≥10 points).

Final determination: ENIGMA BRCA1/2 VCEP Table 3: 1 Very Strong (PVS1) + 1 Strong (PM5) → Pathogenic; point total 13 ≥ 10 threshold for Pathogenic.

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	Met	Nonsense variant NM_007294.4:c.2182A>T (p.Arg728Ter) in BRCA1 exon 10 (legacy exon 11). BRCA1 loss of function is an established disease mechanism. The PTC occurs at codon 728 within the large exon 10 (c.671-4096, codons 224-1366), located >1900 nt upstream of the exon 10-11 junction, predicting nonsense-mediated decay. Per ENIGMA Specification Table 4, BRCA1 exon 10 PTC variants are assigned PVS1 at full (Very Strong) weight.	cspec vcep_specifications_table4_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PS1	N/A	PS1 applies to missense substitutions or splicing variants with a previously classified pathogenic comparator. This is a nonsense (PTC) variant; PS1 is not applicable per ENIGMA specification.	cspec
PS2	N/A	PS2 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification.	cspec
PS3	N/A	PS3/BS3 functional assay codes in ENIGMA Specification Table 9 apply to missense and synonymous variants. This is a nonsense (PTC) variant; the functional consequence (truncation/NMD) is captured by PVS1. PS3 is not applicable.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not met	ENIGMA PS4 requires a case-control study with p-value ≤ 0.05 and OR ≥ 4 (lower CI excludes 2.0). No published case-control study for this specific variant is available. The variant has been observed in affected individuals through clinical testing and is absent from gnomAD, but these observations do not meet the formal PS4 threshold.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not included in the ENIGMA BRCA1/2 VCEP criteria set.
PM1	N/A	PM1 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification.	cspec
PM2	Met	Absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA specification, absence from outbred population controls in gnomAD qualifies for PM2_Supporting.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Met	ENIGMA Specification Table 4 assigns PM5_Strong (PTC) for nonsense variants in BRCA1 exon 10 (legacy exon 11). This exon has multiple proven pathogenic PTC variants, and the PM5_PTC code is supported by sufficient evidence across functional assay, case-control, personal/family history, and CIMBA data per Supplementary Table 1.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	PM6 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification.	cspec
PP1	Not met	ENIGMA PP1 requires quantitative co-segregation analysis yielding an LR ≥ 2.08 (Supporting). No co-segregation likelihood ratio data for this variant was available in the case materials. The variant was not listed in the clinical-history LR spreadsheet (PMID:31853058).
PP2	N/A	PP2 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification.	cspec
PP3	N/A	ENIGMA PP3 applies to missense or in-frame variants inside clinically important functional domains with BayesDel ≥ 0.28, or to variants with predicted splicing impact (SpliceAI ≥ 0.2). This is a nonsense variant with SpliceAI max delta 0.00 and BayesDel 0.18. PP3 is not applicable.	cspec spliceai bayesdel
PP4	Not met	ENIGMA PP4 requires a clinical-history likelihood ratio ≥ 2.08 (Supporting) from multifactorial likelihood clinical data. The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history LR spreadsheet. No other clinical-history LR data is available.	vcep_pmid_31853058_brca1_clinical_history_lr
PP5	N/A	PP5 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification.	cspec
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% in gnomAD v2.1 non-cancer exome or v3.1 non-cancer, non-founder populations. The variant is absent from all gnomAD populations.	gnomad_v2 gnomad_v4
BS1	Not met	ENIGMA BS1 requires FAF > 0.01% (Strong) or FAF > 0.002% and ≤ 0.01% (Supporting) in gnomAD non-cancer subsets. The variant is absent from all gnomAD populations.	gnomad_v2 gnomad_v4
BS2	Not assessed	ENIGMA BS2 requires absence of Fanconi Anemia phenotype features and ≥ 4 points under the Specification Table 8 scoring system. No systematic FA phenotype screening data for carriers of this specific variant is available for review.
BS3	N/A	ENIGMA BS3 functional assay codes (Specification Table 9) apply to missense and synonymous variants. This is a nonsense variant; the functional consequence is captured by PVS1.	cspec
BS4	Not met	ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation in affected family members (LR ≤ 0.48 for Supporting). No BS4-applicable co-segregation data is available for this variant.
BP1	N/A	ENIGMA BP1_Strong applies to silent, missense, or in-frame variants outside clinically important functional domains with SpliceAI ≤ 0.1. This is a nonsense (PTC) variant; BP1 is not applicable.	cspec
BP2	N/A	BP2 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification.	cspec
BP4	N/A	ENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1. This is a nonsense variant; BP4 is not applicable. BayesDel score is 0.18 (>0.15 threshold).	cspec bayesdel
BP5	Not met	ENIGMA BP5 requires a clinical-history LR ≤ 0.48 (Supporting) from multifactorial likelihood data. The variant was not found in the Li et al. 2020 clinical-history LR spreadsheet. No data supports BP5.
BP6	N/A	BP6 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification.	cspec
BP7	N/A	ENIGMA BP7 applies to intronic and silent variants, and to missense/in-frame variants outside clinically important functional domains when mRNA assay shows no damaging effect. This is a nonsense (PTC) variant; BP7 is not applicable.	cspec
BP3	N/A	BP3 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification (captured by bioinformatic tool prediction and domain analysis).
PM3	N/A	PM3 per ENIGMA requires Fanconi Anemia phenotype with co-occurrent variants in trans and specific scoring under Specification Table 6. No FA case data with this variant is available for review in the case materials.
PM4	N/A	PM4 is marked Not Applicable by the ENIGMA BRCA1/2 VCEP specification (not applicable to BRCA1/2).

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