Variant classification summary

NM_007294.4:c.135-1G>T

BRCA1 · NP_009225.1:p.? · NM_007294.4

GRCh37: chr17:41258551 C>A · GRCh38: chr17:43106534 C>A

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.135-1G>T (NP_009225.1:p.?) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar with a pathogenic expert-panel classification.

2

This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 7.14e-06 (2/280296 alleles) and gnomAD v4.1 AF 4.42e-06 (7/1583254 alleles), which is below benign frequency thresholds but does not meet the ENIGMA PM2 requirement for absence from controls.

3

RNA and multifactorial evidence support a damaging splice effect for this variant, including exon 5 deletion in splicing studies, ENIGMA assignment of PVS1 (RNA), a reference-set posterior probability of 0.99999838416, and a BRCA1 clinical-history likelihood ratio of 59.69 across 7 probands, supporting PP4_Strong.

4

In silico splicing analysis predicts a strong splice effect, with a SpliceAI maximum delta score of 0.86, which is consistent with disruption of normal splicing but is not counted separately as PP3 because the same splice evidence is already captured under the PVS1 framework.

Final determination: Pathogenic based on one Very Strong pathogenic criterion together with one Strong pathogenic criterion under the ENIGMA BRCA1/BRCA2 Table 3 combination rules.

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	This BRCA1 variant affects the canonical splice acceptor at c.135-1. BRCA1 loss of function is an established disease mechanism, but the ENIGMA BRCA1 exon-specific table assigns c.135-1G>T to PVS1 (RNA) rather than full-strength generic PVS1 because available RNA data show aberrant splicing with exon 5 deletion, consistent with a damaging loss-of-function effect.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:20020529
PS1	Not assessed	Available evidence does not establish, within the retrieved materials, that this variant should receive PS1 based on a previously classified variant with the same proven splicing consequence at the weight required by the ENIGMA BRCA1 rules.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	This criterion is not used by the ENIGMA BRCA1 specification for this gene-disease context.	cspec
PS3	N/A	Available functional evidence for this variant is RNA-based splicing evidence rather than a protein or combined protein-plus-RNA assay assigned under ENIGMA Table 9. Under the BRCA1 specification, damaging mRNA-only evidence is captured under PVS1 (RNA) rather than PS3.	cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:20020529
PS4	Not assessed	This variant has been reported in affected individuals, but no ethnicity-matched case-control analysis with p-value less than or equal to 0.05 and odds ratio at least 4, with the lower confidence interval excluding 2.0, was identified from the retrieved evidence. ENIGMA also directs clinical-history likelihood ratios to PP4 or BP5 rather than PS4.	cspec clinvar vcep_pmid_31853058_brca1_clinical_history_lr
PM1	N/A	This criterion is not applied as a standalone code in the ENIGMA BRCA1 specification and is instead incorporated into the bioinformatic framework for other variant types.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 7.14e-06 (2/280296 alleles) and in gnomAD v4.1 at AF 4.42e-06 (7/1583254 alleles), so the ENIGMA PM2 requirement for absence from controls is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for co-occurrence with another BRCA1 variant in a proband with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 cannot be assessed from the available data.	cspec
PM4	N/A	This criterion is not used by the ENIGMA BRCA1 specification.	cspec
PM5	N/A	ENIGMA PM5 in BRCA1 is used for protein-termination variants that are already annotated with PVS1 in exons where PM5_PTC is permitted. This splice variant is assigned PVS1 (RNA) rather than a PTC-based PVS1 code, so PM5_PTC is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not used by the ENIGMA BRCA1 specification for this gene-disease context.	cspec
PP1	Not assessed	No quantitative co-segregation likelihood ratio meeting ENIGMA PP1 thresholds was identified in the available evidence, so co-segregation support cannot be assigned.	cspec PMID:15131401 PMID:16528604 PMID:16998791 PMID:18824701
PP2	N/A	This criterion is not used by the ENIGMA BRCA1 specification.	cspec
PP3	N/A	SpliceAI predicts a strong splice effect with a maximum delta score of 0.86, which is above the ENIGMA PP3 threshold of 0.2. However, the generic PVS1 scaffold and ENIGMA guidance state that PP3 should not be stacked when the same splice-effect evidence is already being used for PVS1 in a canonical splice variant, so PP3 is not additionally applied.	cspec spliceai pvs1_variant_assessment
PP4	Met	Variant-specific clinical-history likelihood-ratio evidence supports pathogenicity. In the BRCA1 clinical-history LR table, this variant has LR 59.69 in 7 probands, which is above the ENIGMA PP4_Strong threshold of 18.7.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold. The highest available group maximum filter allele frequency is 2.52e-06 in gnomAD v4.1, which is below the ENIGMA BA1 threshold of greater than 0.001.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Population frequency does not meet the benign strong or supporting thresholds. The highest available group maximum filter allele frequency is 2.52e-06 in gnomAD v4.1, which is below the ENIGMA BS1_Supporting threshold of greater than 2.0e-05 and below the BS1 threshold of greater than 1.0e-04.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	No point-based evidence from unaffected individuals or from individuals lacking features of BRCA1-related Fanconi anemia was identified, so BS2 cannot be assessed from the available data.	cspec
BS3	N/A	No well-established functional evidence showing no damaging effect was identified. Available RNA evidence supports abnormal splicing and is not benign evidence, so BS3 is not applicable.	cspec vcep_supplementarytables_v1_2_2024_11_18 PMID:20020529
BS4	Not assessed	No quantitative lack-of-segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified in the available evidence, so BS4 cannot be assigned.	cspec PMID:15131401 PMID:16528604 PMID:16998791 PMID:18824701
BP1	N/A	BP1 applies to silent, missense, or in-frame variants outside clinically important domains without predicted splice impact. This canonical splice acceptor variant does not fit that rule.	cspec
BP2	N/A	This criterion is not used by the ENIGMA BRCA1 specification.	cspec
BP3	N/A	This criterion is not used by the ENIGMA BRCA1 specification.	cspec
BP4	N/A	BP4 applies when computational evidence predicts no impact. SpliceAI shows a maximum delta score of 0.86, which is well above the ENIGMA no-impact threshold of 0.1, so BP4 is not applicable.	cspec spliceai
BP5	Not met	Variant-specific clinical-history evidence does not support BP5. The observed LR is 59.69 in 7 probands, which is far above the BP5 benign threshold of less than or equal to 0.48 and instead supports PP4_Strong.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not used by the ENIGMA BRCA1 specification.	cspec
BP7	N/A	BP7 is a benign splicing code for variants with no damaging transcript effect. Available RNA evidence shows exon 5 deletion, and computational evidence predicts a strong splice effect with SpliceAI 0.86, so BP7 is not applicable.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18 PMID:20020529

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