Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_007294.4(BRCA1):c.5194-12G>A

CA003343

55451 (ClinVar)

Gene: BRCA1
Condition: BRCA1-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: e65d531b-8a68-477f-8c2e-03dd7faf26c8
Approved on: 2024-06-12
Published on: 2024-06-12

HGVS expressions

NM_007294.4:c.5194-12G>A
NM_007294.4(BRCA1):c.5194-12G>A
NC_000017.11:g.43057147C>T
CM000679.2:g.43057147C>T
NC_000017.10:g.41209164C>T
CM000679.1:g.41209164C>T
NC_000017.9:g.38462690C>T
NG_005905.2:g.160837G>A
ENST00000461574.2:c.5191-12G>A
ENST00000470026.6:c.5194-12G>A
ENST00000473961.6:c.5068-12G>A
ENST00000476777.6:c.5188-12G>A
ENST00000477152.6:c.5116-12G>A
ENST00000478531.6:c.1882-12G>A
ENST00000489037.2:c.5116-12G>A
ENST00000493919.6:c.1744-12G>A
ENST00000494123.6:c.5194-12G>A
ENST00000497488.2:c.4306-12G>A
ENST00000618469.2:c.5194-12G>A
ENST00000634433.2:c.5071-12G>A
ENST00000644379.2:c.5260-12G>A
ENST00000644555.2:c.1744-12G>A
ENST00000652672.2:c.5053-12G>A
ENST00000484087.6:c.1756-12G>A
ENST00000357654.9:c.5194-12G>A
ENST00000471181.7:c.5257-12G>A
ENST00000644379.1:c.1581-12G>A
ENST00000352993.7:c.1768-12G>A
ENST00000357654.7:c.5194-12G>A
ENST00000461221.5:c.*4977-12G>A
ENST00000468300.5:c.1882-12G>A
ENST00000471181.6:c.5257-12G>A
ENST00000491747.6:c.1882-12G>A
ENST00000493795.5:c.5053-12G>A
ENST00000586385.5:c.124-12G>A
ENST00000591534.5:c.667-12G>A
ENST00000591849.5:c.-98-6957G>A
NM_007294.3:c.5194-12G>A
NM_007297.3:c.5053-12G>A
NM_007298.3:c.1882-12G>A
NM_007299.3:c.1882-12G>A
NM_007300.3:c.5257-12G>A
NR_027676.1:n.5330-12G>A
NM_007297.4:c.5053-12G>A
NM_007299.4:c.1882-12G>A
NM_007300.4:c.5257-12G>A
NR_027676.2:n.5371-12G>A
More

Pathogenic

Met criteria codes 3
PP3 PP4_Strong PM2_Supporting
Not Met criteria codes 1
PVS1

Evidence Links 0

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.5194-12G>A variant is an intronic variant occurring in intron 19 of the BRCA1 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.96, predicting an impact on splicing (score threshold >0.20) (PP3 met). This variant was reported to result in aberrant mRNA splicing by partial retention of intron 19 (PMIDs: 21673748, 21394826). Another study reported the same aberration as well as exon 20 skipping, however it also reported a higher proportion of full length transcript (PMID: 31843900) (PVS1 (RNA) not applied due to conflicting evidence). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1126348153 (based on Cosegregation LR=6.5; Pathology LR=12.7; Co-occurrence LR=1.3; Family History LR=10799731), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058). 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 (PM2_Supporting, PP3, PP4_Very strong).
Met criteria codes
PP3
This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and the SpliceAI predictor score is 0.96, predicting an impact on splicing (score threshold >0.20) (PP3 met).
PP4_Strong
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1126348153 (based on Cosegregation LR=6.5; Pathology LR=12.7; Co-occurrence LR=1.3; Family History LR=10799731), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, Internal lab contributors).
PM2_Supporting
This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met).
Not Met criteria codes
PVS1
This variant was reported to result in aberrant mRNA splicing by partial retention of intron 19 (PMIDs: 21673748, 21394826). Another study reported the same aberration as well as exon 20 skipping, however it also reported a higher proportion of full length transcript (PMID: 31843900) (PVS1 (RNA) not applied due to conflicting evidence).
Curation History
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