NM_007294.3:c.615_622dup

BRCA1 · NP_009225.1:p.(Thr208AsnfsTer29) · NM_007294.3

GRCh37: chr17:41247910 G>GTGATTTGT · GRCh38: chr17:43095893 G>GTGATTTGT

Gene: BRCA1 Transcript: NM_007294.3

Final call

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Thr208AsnfsTer29)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA1 c.615_622dup (p.Thr208AsnfsTer29; p.T208Nfs*29) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity, although the available documentation was insufficient to assign BRCA1 ENIGMA PM2_Supporting under the full dataset and coverage requirements.

Under the ENIGMA BRCA1 specification, this frameshift lies in exon 9(10), an exon designated PVS1_N/A and PM5_N/A for protein-truncating variants because rescue of an in-frame transcript is expected, so truncating status alone does not support PVS1 or PM5.

SpliceAI shows a maximum delta score of 0.11, which is below the BRCA1 splice PP3 threshold of 0.20 and above the BP4 no-impact threshold of 0.10; however, the BRCA1 computational rules are not designed to add PP3 or BP4 evidence for this frameshift variant.

Final determination: No pathogenic or benign criteria were met; under the ENIGMA Table 3 combination framework, this results in a classification of Uncertain Significance.

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	This variant is a frameshift change, but the ENIGMA BRCA1 specification designates protein-truncating variants in exon 9(10) as PVS1_N/A because rescue of an in-frame transcript is expected in this region. Therefore, the truncating consequence alone does not support PVS1 for this variant.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	PS1 is used for the same amino-acid change as a previously established pathogenic variant, or for the same predicted splicing effect as a known pathogenic variant. This frameshift duplication does not match that evidence model.	cspec
PS2	N/A	The BRCA1 ENIGMA specification does not use PS2 for this framework.	cspec
PS3	N/A	The BRCA1 ENIGMA PS3 framework uses calibrated functional evidence for specific missense or synonymous variants. No calibrated protein-based functional result was identified for this frameshift duplication, and the available functional tables are not designed to assign PS3 to this variant type.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control data were identified showing a significant enrichment in affected individuals with p-value 0.05 or less and odds ratio 4 or greater. Available evidence does not support PS4 at this time.	clinvar cspec
PM1	N/A	The BRCA1 ENIGMA specification lists PM1 as not applicable in this framework, and this variant is a truncating duplication rather than a missense change evaluated by domain-based PM1 rules.	cspec
PM2	Not assessed	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity. However, the BRCA1 ENIGMA PM2 rule requires absence in the specified control datasets together with adequate regional coverage, and those coverage requirements were not documented here, so PM2_Supporting was not assigned.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	PM3 in the BRCA1 ENIGMA specification is reserved for BRCA1- or BRCA2-related Fanconi anemia with qualifying trans observations and point-based evidence. No such recessive-disease or trans-phase evidence was identified for this variant.	cspec
PM4	N/A	The BRCA1 ENIGMA specification does not use PM4 in this framework.	cspec
PM5	N/A	For BRCA1, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This variant is in exon 9(10), and ENIGMA Table 4 designates protein-truncating variants in this exon as PM5_N/A, so PM5 is not applicable.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The BRCA1 ENIGMA specification does not use PM6 for this framework.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant. Available evidence does not provide a segregation likelihood ratio meeting BRCA1 ENIGMA PP1 thresholds.	clinvar cspec
PP2	N/A	The BRCA1 ENIGMA specification does not use PP2 in this framework.	cspec
PP3	N/A	BRCA1 ENIGMA PP3 applies to missense or in-frame variants in defined functional domains with BayesDel support, or to variants with predicted splice impact when SpliceAI is 0.20 or greater. This variant is a frameshift duplication, and SpliceAI shows a maximum delta score of 0.11, below the splice PP3 threshold, so PP3 was not applied.	cspec spliceai
PP4	Not assessed	No variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant in the reviewed BRCA1 clinical-history materials. Therefore, PP4 was not assigned.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	The BRCA1 ENIGMA specification does not use PP5 in this framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the BRCA1 ENIGMA BA1 frequency threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the BRCA1 ENIGMA BS1 frequency thresholds.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	BS2 in the BRCA1 ENIGMA framework requires point-based evidence from individuals without features of recessive disease, specifically Fanconi anemia. No such proband-level evidence was identified for this variant.	cspec
BS3	N/A	The BRCA1 ENIGMA BS3 framework uses calibrated functional evidence for specific missense or synonymous variants. No calibrated functional evidence showing no damaging effect was identified for this frameshift duplication.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant. Available evidence does not provide a segregation likelihood ratio low enough to support BS4.	clinvar cspec
BP1	N/A	BP1_Strong in the BRCA1 ENIGMA specification is used for silent, missense, or in-frame variants outside defined functional domains with no predicted splice effect. This frameshift duplication does not match that evidence model.	cspec
BP2	N/A	The BRCA1 ENIGMA specification does not use BP2 in this framework.	cspec
BP3	N/A	The BRCA1 ENIGMA specification does not use BP3 in this framework.	cspec
BP4	N/A	BRCA1 ENIGMA BP4 applies to selected missense, in-frame, silent, or intronic variants with no predicted splice impact, including SpliceAI 0.10 or less in the relevant contexts. This variant is a frameshift duplication, and SpliceAI is 0.11, so BP4 was not applied.	cspec spliceai
BP5	Not assessed	No variant-level clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant in the reviewed BRCA1 clinical-history materials. Therefore, BP5 was not assigned.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	The BRCA1 ENIGMA specification does not use BP6 in this framework.	cspec
BP7	N/A	BRCA1 ENIGMA BP7 is used for silent or intronic variants with evidence against splice disruption, or for RNA evidence showing no damaging transcript effect in eligible variant classes. This frameshift duplication does not match that evidence model.	cspec spliceai

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