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.2155A>G (p.Lys719Glu)

CA001442

37452 (ClinVar)

Gene: BRCA1
Condition: breast-ovarian cancer, familial, susceptibility to, 1
Inheritance Mode: Autosomal dominant inheritance
UUID: fd4bcbc3-5cf5-46ae-b827-465fec09e761

HGVS expressions

NM_007294.4:c.2155A>G
NM_007294.4(BRCA1):c.2155A>G (p.Lys719Glu)
NC_000017.11:g.43093376T>C
CM000679.2:g.43093376T>C
NC_000017.10:g.41245393T>C
CM000679.1:g.41245393T>C
NC_000017.9:g.38498919T>C
NG_005905.2:g.124608A>G
ENST00000354071.8:n.2219A>G
ENST00000461574.2:c.2155A>G
ENST00000470026.6:c.2155A>G
ENST00000473961.6:c.2029A>G
ENST00000476777.6:c.2152A>G
ENST00000477152.6:c.2077A>G
ENST00000478531.6:c.784+1368A>G
ENST00000489037.2:c.2077A>G
ENST00000493919.6:c.646+1368A>G
ENST00000494123.6:c.2155A>G
ENST00000497488.2:c.1267A>G
ENST00000618469.2:c.2155A>G
ENST00000634433.2:c.2032A>G
ENST00000644379.2:c.2155A>G
ENST00000644555.2:c.646+1368A>G
ENST00000652672.2:c.2014A>G
ENST00000484087.6:c.664+1368A>G
ENST00000700182.1:c.706+1368A>G
ENST00000357654.9:c.2155A>G
ENST00000471181.7:c.2155A>G
ENST00000352993.7:c.671-2344A>G
ENST00000354071.7:c.2155A>G
ENST00000357654.7:c.2155A>G
ENST00000461221.5:c.*1938A>G
ENST00000468300.5:c.787+1368A>G
ENST00000471181.6:c.2155A>G
ENST00000478531.5:c.784+1368A>G
ENST00000484087.5:c.409+1368A>G
ENST00000487825.5:c.412+1368A>G
ENST00000491747.6:c.787+1368A>G
ENST00000493795.5:c.2014A>G
ENST00000493919.5:c.646+1368A>G
ENST00000586385.5:c.5-29425A>G
ENST00000591534.5:c.-43-18855A>G
ENST00000591849.5:c.-99+31895A>G
ENST00000634433.1:c.2032A>G
NM_007294.3:c.2155A>G
NM_007297.3:c.2014A>G
NM_007298.3:c.787+1368A>G
NM_007299.3:c.787+1368A>G
NM_007300.3:c.2155A>G
NR_027676.1:n.2291A>G
NM_007297.4:c.2014A>G
NM_007299.4:c.787+1368A>G
NM_007300.4:c.2155A>G
NR_027676.2:n.2332A>G

Benign

Met criteria codes 3
BP5_Strong BS1 BP1_Strong

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.2155A>G variant in BRCA1 is a missense variant predicted to cause substitution of Lysine by Glutamic acid at amino acid 719 (p.Lys719Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 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). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0000515 (based on Family History LR= 0.0000515), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31853058). 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 (BS1, BP1_Strong, BP5_Very strong).
Met criteria codes
BP5_Strong
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0000515 (based on Family History LR= 0.0000515), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID 31131967).
BS1
The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.0003 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met).
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).
Approved on: 2024-04-23
Published on: 2024-04-23
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