NM_007294.4:c.2063del

BRCA1 · NP_009225.1:p.(Thr688LysfsTer13) · NM_007294.4

GRCh37: chr17:41245484 TG>T · GRCh38: chr17:43093467 TG>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Pathogenic

PVS1_VeryStrong PM5_Strong PM2_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Thr688LysfsTer13)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA1 c.2063del (p.Thr688LysfsTer13; p.T688Kfs*13) variant has not been observed in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.

This frameshift deletion occurs in BRCA1 exon 10 (legacy exon 11) and is predicted to introduce a premature termination codon; under the ENIGMA BRCA1 specification, truncating variants in this exon meet PVS1 and the exon also carries PM5_Strong (PTC).

SpliceAI predicts no significant additional splice impact for this deletion, with a maximum delta score of 0.00.

Final determination: Pathogenic based on 1 Very Strong pathogenic criterion (PVS1) and 1 Strong pathogenic criterion (PM5) 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 variant is a frameshift deletion in BRCA1 exon 10 (legacy exon 11) predicted to cause p.(Thr688LysfsTer13). Under the ENIGMA BRCA1 specification, truncating variants in this exon meet PVS1, consistent with BRCA1 loss of function as an established disease mechanism.	cspec vcep_specifications_table4_v1_2_2024_11_18 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This is a frameshift deletion, not a missense variant and not an alternate nucleotide change with the same defined splicing effect as a previously classified pathogenic variant, so PS1 does not apply.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	The ENIGMA BRCA1 specification lists PS2 as not applicable in this framework.	cspec
PS3	Not assessed	No variant-specific calibrated functional study result was identified for this frameshift variant in the curated ENIGMA functional assay resources, so PS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control study or quantified enrichment data were identified for this exact variant, so PS4 cannot be applied.
PM1	N/A	PM1 is not used for this frameshift variant in the BRCA1 ENIGMA framework, which applies domain-based PM1 logic to specific missense contexts rather than truncating variants.	cspec vcep_appendices_v1_2_2024_11_18
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the ENIGMA BRCA1 PM2 threshold for absence from population controls.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with another BRCA1 variant in an individual with BRCA1-related Fanconi anemia, so PM3 was not applied.	cspec
PM4	N/A	The ENIGMA BRCA1 specification lists PM4 as not applicable in this framework.	cspec
PM5	Met	This protein-truncating variant occurs in BRCA1 exon 10 (legacy exon 11), an exon designated PM5_Strong (PTC) in the ENIGMA BRCA1 exon table, indicating that different proven pathogenic protein-truncating variants have been observed in this exon.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The ENIGMA BRCA1 specification lists PM6 as not applicable in this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not applied.
PP2	N/A	The ENIGMA BRCA1 specification lists PP2 as not applicable in this framework.	cspec
PP3	N/A	PP3 in the ENIGMA BRCA1 framework is used for qualifying missense, in-frame, silent, or intronic variants with predicted damaging protein or splicing effects. This variant is a frameshift deletion, so PP3 does not apply.	cspec spliceai
PP4	Not assessed	No variant-level clinical-history likelihood ratio entry was identified for this exact variant in the BRCA1 ENIGMA clinical-history resource, so PP4 was not applied.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	The ENIGMA BRCA1 specification lists PP5 as not applicable 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 BA1 population 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 exceed the BS1 population frequency thresholds.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying observations in individuals lacking features of BRCA1-related Fanconi anemia were identified for this variant, so BS2 was not applied.	cspec
BS3	Not assessed	No variant-specific calibrated functional study showing no damaging effect was identified for this frameshift variant in the curated ENIGMA functional assay resources, so BS3 was not applied.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not applied.
BP1	N/A	BP1 in the ENIGMA BRCA1 framework is used for qualifying silent, missense, or in-frame variants outside clinically important domains without predicted splicing impact. This frameshift deletion does not fit that rule.	cspec
BP2	N/A	The ENIGMA BRCA1 specification lists BP2 as not applicable in this framework.	cspec
BP3	N/A	The ENIGMA BRCA1 specification lists BP3 as not applicable in this framework.	cspec
BP4	N/A	BP4 in the ENIGMA BRCA1 framework is used for qualifying missense, in-frame, silent, or intronic variants without predicted impact. This variant is a frameshift deletion, so BP4 does not apply.	cspec spliceai
BP5	Not assessed	No variant-level clinical-history likelihood ratio entry was identified for this exact variant in the BRCA1 ENIGMA clinical-history resource, so BP5 was not applied.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	The ENIGMA BRCA1 specification lists BP6 as not applicable in this framework.	cspec
BP7	N/A	BP7 in the ENIGMA BRCA1 framework is used for qualifying silent or intronic variants, and in limited RNA-specific situations for other variant classes. This frameshift deletion does not meet those use conditions.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.