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]
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  • 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.3082C>T (p.Arg1028Cys)

CA002019

37506 (ClinVar)

Gene: BRCA1
Condition: BRCA1-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2061883d-ba9a-4fc8-92c5-d24655eaf5b3

HGVS expressions

NM_007294.4:c.3082C>T
NM_007294.4(BRCA1):c.3082C>T (p.Arg1028Cys)
NC_000017.11:g.43092449G>A
CM000679.2:g.43092449G>A
NC_000017.10:g.41244466G>A
CM000679.1:g.41244466G>A
NC_000017.9:g.38497992G>A
NG_005905.2:g.125535C>T
ENST00000354071.8:n.3146C>T
ENST00000461574.2:c.3082C>T
ENST00000470026.6:c.3082C>T
ENST00000473961.6:c.2956C>T
ENST00000476777.6:c.3079C>T
ENST00000477152.6:c.3004C>T
ENST00000478531.6:c.785-1417C>T
ENST00000489037.2:c.3004C>T
ENST00000493919.6:c.647-1417C>T
ENST00000494123.6:c.3082C>T
ENST00000497488.2:c.2194C>T
ENST00000618469.2:c.3082C>T
ENST00000634433.2:c.2959C>T
ENST00000644379.2:c.3082C>T
ENST00000644555.2:c.647-1417C>T
ENST00000652672.2:c.2941C>T
ENST00000484087.6:c.665-1417C>T
ENST00000700182.1:c.707-1417C>T
ENST00000357654.9:c.3082C>T
ENST00000471181.7:c.3082C>T
ENST00000352993.7:c.671-1417C>T
ENST00000354071.7:c.3082C>T
ENST00000357654.7:c.3082C>T
ENST00000461221.5:c.*2865C>T
ENST00000468300.5:c.788-1417C>T
ENST00000471181.6:c.3082C>T
ENST00000478531.5:c.785-1417C>T
ENST00000484087.5:c.410-1417C>T
ENST00000487825.5:c.413-1417C>T
ENST00000491747.6:c.788-1417C>T
ENST00000493795.5:c.2941C>T
ENST00000493919.5:c.647-1417C>T
ENST00000586385.5:c.5-28498C>T
ENST00000591534.5:c.-43-17928C>T
ENST00000591849.5:c.-99+32822C>T
NM_007294.3:c.3082C>T
NM_007297.3:c.2941C>T
NM_007298.3:c.788-1417C>T
NM_007299.3:c.788-1417C>T
NM_007300.3:c.3082C>T
NR_027676.1:n.3218C>T
NM_007297.4:c.2941C>T
NM_007299.4:c.788-1417C>T
NM_007300.4:c.3082C>T
NR_027676.2:n.3259C>T

Benign

Met criteria codes 4
BP1_Strong BS2_Supporting BP5_Strong BS3
Not Met criteria codes 3
BA1 PM2 BS1

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.3082C>T variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 1028 (p.Arg1028Cys). 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 missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold < 0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). This variant has been observed in one individual with features considered inconsistent with an FA-associated phenotype, variant is homozygous (total score 1 point) (BS2_Supporting met; PMID: 29435075). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0009 (based on Cosegregation LR=0.131; Pathology LR=0.056; Co-occurrence LR= 1.527; Family History LR= 0.081), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BS3, BS2_Supporting, BP5_Very strong).
Met criteria codes
BP1_Strong
This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold < 0.1) (BP1_Strong met).
BS2_Supporting
This variant has been observed in one individual with features considered inconsistent with an FA-associated phenotype, variant is homozygous (total score 1 point) (BS2_Supporting met; PMID: 29435075).
BP5_Strong
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0009 (based on Cosegregation LR=0.131; Pathology LR=0.056; Co-occurrence LR= 1.527; Family History LR= 0.081), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31131967).
BS3
Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met).
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).
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).
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).
Approved on: 2024-06-12
Published on: 2024-06-11
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