Variant: NM_007294.4(BRCA1):c.4186-1787_4358-1668dup

267530 (ClinVar)

Gene: BRCA1

Condition: BRCA1-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 9dabe68a-20a3-4a73-b261-f458820fcca3

Approved on: 2024-06-12

Published on: 2024-06-11

HGVS expressions

NM_007294.4:c.4186-1787_4358-1668dup
NM_007294.4(BRCA1):c.4186-1787_4358-1668dup

Pathogenic

• Met criteria codes: PVS1 PM5_Strong

• Not Met criteria codes: PM2

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.0.0

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.4186-1787_4358-1668dup variant in BRCA1 is a large duplication variant. This variant has been previously reported as a duplication of exon 13 (legacy exon numbering, PMID: 10827109), c.4186-?_4357+?dup (uncharacterized breakpoints), BRCA1 ~6kb dup (PMID: 9915971), c.4186-1787_4357+4122dup (PMID: 29446198) and c.4186-1832_4358-1634dup (PMID: 30054569). This duplication variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Confirmed tandem duplication of exon 12 is predicted to cause a premature stop codon in inserted biologically-relevant-exon 12 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTCs in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 12 (PM5_Strong (PTC)). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC)).

Met criteria codes

• PVS1: Confirmed tandem duplication of exon 12 is predicted to cause a premature stop codon in inserted biologically-relevant-exon 12 leading to nonsense mediated decay (PVS1 met).
• PM5_Strong: The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTCs in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 12 (PM5_Strong (PTC)).

Not Met criteria codes

• PM2: This duplication variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met).