Variant: NM_007294.4(BRCA1):c.5333-36_5406+400del

CA10602571

267601 (ClinVar)

Gene: BRCA1

Condition: BRCA1-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: c5a3fb71-22c6-4f15-bbf5-51f07ad6eff3

Approved on: 2024-06-12

Published on: 2024-06-12

HGVS expressions

NM_007294.4:c.5333-36_5406+400del
NM_007294.4(BRCA1):c.5333-36_5406+400del
NC_000017.11:g.43048723_43049232del
CM000679.2:g.43048723_43049232del
NC_000017.10:g.41200740_41201249del
CM000679.1:g.41200740_41201249del
NC_000017.9:g.38454266_38454775del
NG_005905.2:g.168754_169263del
ENST00000461574.2:c.5330-36_5403+400del
ENST00000470026.6:c.5333-36_5406+400del
ENST00000473961.6:c.5207-36_5280+400del
ENST00000476777.6:c.5327-36_5400+400del
ENST00000477152.6:c.5255-36_5328+400del
ENST00000478531.6:c.2021-36_2094+400del
ENST00000489037.2:c.5255-36_5328+400del
ENST00000493919.6:c.1883-36_1956+400del
ENST00000494123.6:c.5333-36_5406+400del
ENST00000497488.2:c.4445-36_4518+400del
ENST00000618469.2:c.5333-36_5406+400del
ENST00000634433.2:c.5210-36_5283+400del
ENST00000644379.2:c.5399-36_5472+400del
ENST00000644555.2:c.1883-36_1956+400del
ENST00000652672.2:c.5192-36_5265+400del
ENST00000484087.6:c.1895-36_1968+400del
ENST00000700081.1:n.1180_1289+400del
ENST00000357654.9:c.5333-36_5406+400del
ENST00000471181.7:c.5396-36_5469+400del
ENST00000644379.1:c.1720-36_1793+400del
ENST00000352993.7:c.1907-36_1980+400del
ENST00000357654.7:c.5333-36_5406+400del
ENST00000461221.5:c.*5116-36_*5189+400del
ENST00000468300.5:c.2021-1527_2021-1018del
ENST00000471181.6:c.5396-36_5469+400del
ENST00000491747.6:c.2021-36_2094+400del
ENST00000493795.5:c.5192-36_5265+400del
ENST00000586385.5:c.263-36_336+400del
ENST00000591534.5:c.806-36_879+400del
ENST00000591849.5:c.32-36_105+400del
NM_007294.3:c.5333-36_5406+400del
NM_007297.3:c.5192-36_5265+400del
NM_007298.3:c.2021-36_2094+400del
NM_007299.3:c.2021-1527_2021-1018del
NM_007300.3:c.5396-36_5469+400del
NR_027676.1:n.5469-36_5542+400del
NM_007297.4:c.5192-36_5265+400del
NM_007299.4:c.2021-1527_2021-1018del
NM_007300.4:c.5396-36_5469+400del
NR_027676.2:n.5510-36_5583+400del

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.5333-36_5406+400del variant in BRCA1 is a large deletion variant. This deletion 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). This variant has been previously reported as deletion exon 22 (legacy exon numbering) in PMIDs: 9354803, 18431737, 22544547, and 24065545. Deletion of exon 21 variant is predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (sequence upstream of BRCA1 p.Leu1854 is disrupted) (PVS1 met). The ENIGMA BRCA1/BRCA2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant within BRCA1 exon 23 (PTC occurs before p.I1855) (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: Deletion of exon 21 variant is predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (sequence upstream of BRCA1 p.Leu1854 is disrupted) (PVS1 met).
• PM5_Strong: The ENIGMA BRCA1/BRCA2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant within BRCA1 exon 23 (PTC occurs before p.I1855) (PM5_Strong (PTC)).

Not Met criteria codes

• PM2: This deletion 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).