Variant classification summary

NM_007294.4:c.4689C>G

BRCA1 · NP_009225.1:p.(Tyr1563Ter) · NM_007294.4

GRCh37: chr17:41223242 G>C · GRCh38: chr17:43071225 G>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1 very strong PM5 strong PP4 strong PP5 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Tyr1563Ter)

gnomAD AF

3.097835851873881e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.4:c.4689C>G (p.Tyr1563Ter) is a nonsense variant in BRCA1 exon 15(16) that creates a premature termination codon.

2

PVS1 is met at Very Strong strength: loss-of-function is an established disease mechanism for BRCA1, and the ENIGMA Table 4 PVS1 decision framework assigns full-strength PVS1 to protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the PTC at codon 1563 is upstream of the annotated NMD escape boundary.

3

PM5_Strong (PTC) is met: ENIGMA Table 4 assigns PM5_Strong for PTC variants in exon 15(16), supported by 15 total evidence points in Supplementary Table ST1 spanning functional assay data, clinical history, and population-level evidence.

4

PP4_Strong is met: the clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 159.82 (17 probands), greatly exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history is highly consistent with known pathogenic BRCA1 variants.

5

PM2 is not met: the variant is observed at extremely low frequency in gnomAD (v2.1: 1/250,704; v4.1: 5/1,614,030). Under ENIGMA, a single observation in an outbred population is not considered informative for PM2 assignment.

6

PS3 is not met: no variant-specific functional assay data exist for c.4689C>G in the ENIGMA Table 9 curated functional assay results or in the reviewed literature.

7

No benign criteria are met. The population frequencies are far below BS1 and BA1 thresholds, no functional data support BS3, and the clinical history LR is in the pathogenic direction.

8

Combined classification: PVS1 (Very Strong) + PM5_Strong (Strong) + PP4_Strong (Strong) meets ENIGMA Table 3 pathogenic combination rule (≥1 Very Strong + ≥1 Strong).

Final determination: ENIGMA BRCA1/BRCA2 VCEP v1.2 Table 3: one Very Strong criterion (PVS1) plus at least one Strong criterion (PM5_Strong, PP4_Strong) classifies the variant as 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.4689C>G (p.Tyr1563Ter) in BRCA1 exon 15(16), a gene where loss-of-function is an established disease mechanism for hereditary breast and ovarian cancer. ENIGMA Table 4 assigns PVS1 at full strength for protein termination codon variants in exon 15(16). Nonsense-mediated decay is predicted as the premature termination codon is located well upstream of the last exon-exon junction and outside the NMD escape boundary annotated in the ENIGMA specification.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PS1	N/A	PS1 under ENIGMA v1.2 applies to predicted missense substitutions or exonic/intronic variants with same predicted splicing impact as a previously classified pathogenic variant. This is a nonsense variant; PS1 does not apply to protein termination codon variants in this framework.
PS2	N/A	ENIGMA v1.2 declares PS2 Not Applicable: BRCA1/2-related cancers occur relatively commonly; no information is available to calibrate the predictive capacity of de novo occurrences.	cspec
PS3	Not met	ENIGMA Table 9 contains no pre-assigned PS3 code for c.4689C>G, and no variant-specific functional data were identified in the literature. Under the ENIGMA framework, functional evidence for protein termination codon variants is captured by PVS1 and PM5_PTC rather than PS3, which is applied primarily to missense variants with calibrated functional assay results.	vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control study satisfying ENIGMA PS4 requirements (p ≤ 0.05, OR ≥ 4, lower confidence interval excludes 2.0, ethnicity- and country-matched controls) was identified for c.4689C>G in the case materials.
PS5	N/A	PS5 under generic ACMG/AMP applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been seen. This is a nonsense variant (p.Tyr1563Ter); PS5 does not apply.
PM1	N/A	ENIGMA v1.2 declares PM1 Not Applicable; mutational hotspot and critical functional domain information is considered through the bioinformatic analysis codes (PP3/BP4) and the domain-specific framework rules in this VCEP.	cspec
PM2	Not met	ENIGMA PM2_Supporting requires absence from gnomAD controls in outbred populations. c.4689C>G is present in gnomAD v2.1 (1/250,704 alleles; AF=3.99e-6; European non-Finnish) and gnomAD v4.1 (5/1,614,030 alleles; AF=3.10e-6; European non-Finnish). ENIGMA specifically states that observation of a variant only once in a gnomAD outbred population is not informative; PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PM5	Met	ENIGMA Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA1 exon 15(16). This exon is not among the PM5_N/A exons (E21(22), E6(7), E7(8)). Supplementary Table ST1 confirms PM5_Strong with 15 total evidence points: functional assay PTC loss-of-function (4 points), functional assay missense loss-of-function (2 points), personal and family history LR (4 points), standardised incidence ratio (4 points), and CIMBA (1 point). Multiple proven pathogenic PTC variants have been observed in this exon.	vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 cspec
PM6	N/A	ENIGMA v1.2 declares PM6 Not Applicable: BRCA1/2-related cancers occur relatively commonly; no information to calibrate the predictive capacity of de novo occurrences.	cspec
PP1	Not assessed	No quantitative co-segregation analysis data meeting ENIGMA PP1 thresholds (LR ≥ 2.08 by Bayes score) was available for c.4689C>G in the case materials.
PP2	N/A	ENIGMA v1.2 declares PP2 Not Applicable.	cspec
PP3	N/A	PP3 under ENIGMA v1.2 applies to (a) missense or in-frame variants within a clinically important functional domain with BayesDel no-AF score ≥ 0.28, or (b) variants with SpliceAI ≥ 0.2 predicting altered splicing for silent/missense/in-frame/intronic variants. This is a nonsense variant with SpliceAI max delta 0.03 showing no predicted splicing impact; PP3 does not apply.	spliceai cspec
PP4	Met	Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio for c.4689C>G is 159.82 (LOG(LR)=5.074, N=17 probands), exceeding the ENIGMA PP4_Strong threshold of LR ≥ 18.7. The variant's personal and family cancer history profile is highly consistent with that observed for known pathogenic BRCA1 variants.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr cspec
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	cspec clinvar
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) > 0.1% in gnomAD v2.1 or v3.1 non-founder populations. The maximum allele frequency for c.4689C>G is 4.24e-6 (0.00042%) in gnomAD v4.1 European non-Finnish, far below the BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	ENIGMA BS1_Supporting requires FAF > 0.002% in gnomAD non-founder populations; BS1_Strong requires FAF > 0.01%. The maximum allele frequency for c.4689C>G is 4.24e-6 (0.00042%), below both the Supporting and Strong thresholds.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No individual-level co-occurrence data with Fanconi Anemia phenotype or healthy adult observation meeting ENIGMA Table 8 criteria was available for c.4689C>G in the case materials.
BS3	Not met	ENIGMA Table 9 contains no pre-assigned BS3 code for c.4689C>G. No well-established functional studies demonstrating no damaging effect on protein function were identified for this variant in the literature.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative co-segregation analysis data showing lack of segregation meeting ENIGMA BS4 thresholds was available for c.4689C>G in the case materials.
BP1	N/A	ENIGMA BP1_Strong applies only to silent substitution, missense, or in-frame insertion/deletion/delins variants outside a clinically important functional domain with SpliceAI ≤ 0.1. This is a nonsense variant; BP1 does not apply.	cspec
BP2	N/A	ENIGMA v1.2 declares BP2 Not Applicable; applied only in the context of BS2.	cspec
BP4	N/A	ENIGMA BP4 applies only to missense/in-frame variants within clinically important functional domains with BayesDel ≤ 0.15 and SpliceAI ≤ 0.1, or to silent/intronic variants with SpliceAI ≤ 0.1. This is a nonsense variant; BP4 does not apply.	cspec
BP5	Not met	The Li et al. 2020 clinical-history LR for c.4689C>G is 159.82 in the pathogenic direction. ENIGMA BP5 requires LR ≤ 0.48 (Supporting) or lower; the observed LR is far above the benign thresholds.	PMID:31853058 vcep_pmid_31853058_brca1_clinical_history_lr
BP6	N/A	ENIGMA v1.2 declares BP6 Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	ENIGMA BP7 applies to silent/intronic variants with mRNA assay data showing no splicing effect, or to missense/in-frame variants outside clinically important functional domains with well-established mRNA splicing assays. This is a nonsense variant; BP7 does not apply.	cspec

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