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.135-1G>T

CA000895

37404 (ClinVar)

Gene: BRCA1
Condition: BRCA1-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9ce06200-8cef-417f-a140-13599174fb72
Approved on: 2024-06-12
Published on: 2024-06-11

HGVS expressions

NM_007294.4:c.135-1G>T
NM_007294.4(BRCA1):c.135-1G>T
NC_000017.11:g.43106534C>A
CM000679.2:g.43106534C>A
NC_000017.10:g.41258551C>A
CM000679.1:g.41258551C>A
NC_000017.9:g.38512077C>A
NG_005905.2:g.111450G>T
ENST00000354071.8:n.199-1G>T
ENST00000461574.2:c.135-1G>T
ENST00000470026.6:c.135-1G>T
ENST00000473961.6:c.135-1G>T
ENST00000476777.6:c.135-1G>T
ENST00000477152.6:c.135-1578G>T
ENST00000478531.6:c.135-1G>T
ENST00000489037.2:c.135-1578G>T
ENST00000493919.6:c.-7-1G>T
ENST00000494123.6:c.135-1G>T
ENST00000497488.2:c.-218-11674G>T
ENST00000618469.2:c.135-1G>T
ENST00000634433.2:c.135-1G>T
ENST00000644379.2:c.135-1G>T
ENST00000644555.2:c.-7-1G>T
ENST00000652672.2:c.-7-1G>T
ENST00000484087.6:c.135-1G>T
ENST00000700182.1:c.135-1578G>T
ENST00000700183.1:c.*71-1G>T
ENST00000700184.1:n.378-1G>T
ENST00000357654.9:c.135-1G>T
ENST00000471181.7:c.135-1G>T
ENST00000642945.1:c.*9-1G>T
ENST00000644555.1:c.-7-1G>T
ENST00000652672.1:c.-7-1G>T
ENST00000352993.7:c.135-1G>T
ENST00000354071.7:c.135-1G>T
ENST00000357654.7:c.135-1G>T
ENST00000461221.5:c.135-1G>T
ENST00000461798.5:c.135-1G>T
ENST00000468300.5:c.135-1G>T
ENST00000470026.5:c.135-1G>T
ENST00000471181.6:c.135-1G>T
ENST00000476777.5:c.135-1G>T
ENST00000477152.5:c.135-1578G>T
ENST00000478531.5:c.135-1G>T
ENST00000489037.1:c.135-1578G>T
ENST00000491747.6:c.135-1G>T
ENST00000492859.5:c.*71-1G>T
ENST00000493795.5:c.-7-1G>T
ENST00000493919.5:c.-7-1G>T
ENST00000494123.5:c.135-1G>T
ENST00000497488.1:c.-218-11674G>T
ENST00000586385.5:c.4+18648G>T
ENST00000591534.5:c.-44+18737G>T
ENST00000591849.5:c.-99+18737G>T
ENST00000634433.1:c.135-1G>T
NM_007294.3:c.135-1G>T
NM_007297.3:c.-7-1G>T
NM_007298.3:c.135-1G>T
NM_007299.3:c.135-1G>T
NM_007300.3:c.135-1G>T
NR_027676.1:n.296-1G>T
NM_007297.4:c.-7-1G>T
NM_007299.4:c.135-1G>T
NM_007300.4:c.135-1G>T
NR_027676.2:n.337-1G>T
More

Pathogenic

Met criteria codes 3
PVS1 PS3 PP4_Strong
Not Met criteria codes 3
BA1 BS1 PM2

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.135-1G>T variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 3 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RNAseq demonstrated that the variant impacts splicing by resulting in skipping of exon 4 from the transcript (PMID: 30101128). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 234999878.51 (based on Cosegregation LR=9528; Pathology LR=2.009; Family History LR=12277.7), 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 (PVS1 (RNA), PS3, PP4_Very strong).
Met criteria codes
PVS1
This variant is reported to result in aberrant mRNA splicing. RNAseq demonstrated that the variant impacts splicing by resulting in skipping of exon 4 from the transcript (PMID: 30101128). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met).
PS3
Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met).
PP4_Strong
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 234999878.51 (based on Cosegregation LR=9528; Pathology LR=2.009; Family History LR=12277.7), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967).
Not Met criteria codes
BA1
This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
BS1
This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
PM2
This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
Curation History
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