Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_007294.4(BRCA1):c.5152+6T>C

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA003291

125777 (ClinVar)

Gene: BRCA1

Condition: BRCA1-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 626ebdc5-310f-45de-8bbc-09402b1e60b1

Approved on: 2025-08-21

Published on: 2025-08-21

HGVS expressions

NM_007294.4:c.5152+6T>C

NM_007294.4(BRCA1):c.5152+6T>C

NC_000017.11:g.43063868A>G

CM000679.2:g.43063868A>G

NC_000017.10:g.41215885A>G

CM000679.1:g.41215885A>G

NC_000017.9:g.38469411A>G

NG_005905.2:g.154116T>C

ENST00000461574.2:c.5149+6T>C

ENST00000470026.6:c.5152+6T>C

ENST00000473961.6:c.5026+6T>C

ENST00000476777.6:c.5146+6T>C

ENST00000477152.6:c.5074+6T>C

ENST00000478531.6:c.1840+6T>C

ENST00000489037.2:c.5074+6T>C

ENST00000493919.6:c.1702+6T>C

ENST00000494123.6:c.5152+6T>C

ENST00000497488.2:c.4264+6T>C

ENST00000618469.2:c.5152+6T>C

ENST00000634433.2:c.5029+6T>C

ENST00000644379.2:c.5218+6T>C

ENST00000644555.2:c.1702+6T>C

ENST00000652672.2:c.5011+6T>C

ENST00000484087.6:c.1714+6T>C

ENST00000357654.9:c.5152+6T>C

ENST00000471181.7:c.5215+6T>C

ENST00000644379.1:c.1539+6T>C

ENST00000352993.7:c.1726+6T>C

ENST00000357654.7:c.5152+6T>C

ENST00000461221.5:c.*4935+6T>C

ENST00000468300.5:c.1840+6T>C

ENST00000471181.6:c.5215+6T>C

ENST00000478531.5:c.1840+6T>C

ENST00000484087.5:c.1465+6T>C

ENST00000491747.6:c.1840+6T>C

ENST00000493795.5:c.5011+6T>C

ENST00000493919.5:c.1702+6T>C

ENST00000586385.5:c.82+6T>C

ENST00000591534.5:c.625+6T>C

ENST00000591849.5:c.-98-13678T>C

NM_007294.3:c.5152+6T>C

NM_007297.3:c.5011+6T>C

NM_007298.3:c.1840+6T>C

NM_007299.3:c.1840+6T>C

NM_007300.3:c.5215+6T>C

NR_027676.1:n.5288+6T>C

NM_007297.4:c.5011+6T>C

NM_007299.4:c.1840+6T>C

NM_007300.4:c.5215+6T>C

NR_027676.2:n.5329+6T>C

Pathogenic

PS3 PM2_Supporting PVS1

BP5 PP4 PP3

Evidence Links 0

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.5152+6T>C variant is an intronic variant occurring in intron 17(18) 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). Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.7, predicting an impact on splicing (score threshold >0.20) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by exon skipping (PMIDs: 32123317, 32761968). The percent reference (full-length) and aberrant transcripts produced from the variant allele is not stated, however assessment of gel electrophoresis shows apparent (near) complete splicing effect. The complete splicing effect has been confirmed in an allele-specific RT-PCR assay by an Internal lab contributor. Final code strength determined by the rubric: PVS1 (RNA). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.65 (based on Co-occurrence LR=1.07; Family History LR=0.61), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor). 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, PS3, PVS1 (RNA)).

PS3

Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met).

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).

PVS1

This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by exon skipping (PMIDs: 32123317, 32761968). The percent reference (full-length) and aberrant transcripts produced from the variant allele is not stated, however assessment of gel electrophoresis shows apparent (near) complete splicing effect. The complete splicing effect has been confirmed in an allele-specific RT-PCR assay by an Internal lab contributor. Final code strength determined by the rubric: PVS1 (RNA).

BP5

Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.65 (based on Co-occurrence LR=1.07; Family History LR=0.61), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; Internal lab contributor).

PP4

PP3

This BRCA1 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.7, predicting an impact on splicing (score threshold >0.20) (PP3 not applied because a PVS1 code is met).

Curation History

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