The BRCA1 NM_007294.3:c.2155A>G (NP_009225.1:p.(Lys719Glu), NP_009225.1:p.(K719E)) variant has not been observed in COSMIC and has been reported in ClinVar with a current expert-panel Benign classification, although older laboratory submissions include uncertain significance and likely benign assertions.1 This variant is present in population databases, including gnomAD v2.1 and v4.1, with grpmax FAF values of 0.00062195 and 0.00068503, respectively, which are above the ENIGMA BS1 threshold of 0.0001 but below the BA1 threshold of 0.001.2 Multifactorial clinical-history evidence is in the benign direction, with a BRCA1 clinical-history likelihood ratio of 0.0137 from 10 probands, meeting BP5_Strong and arguing against pathogenicity.3 In silico evidence does not support a damaging effect in the ENIGMA BRCA1 framework: SpliceAI predicts no splice impact (max delta score 0.00), BayesDel is -0.216062, and the missense change lies outside the BRCA1 domains used for PP3/BP4, supporting BP1_Strong rather than PP3.4
BRCA1
Final classification
Benign
BRCA1 c.2155A>G · p.Lys719Glu
BRCA1
The BRCA1 NM_007294.3:c.2155A>G (NP_009225.1:p.(Lys719Glu), NP_009225.1:p.(K719E)) variant has not been observed in COSMIC and has been reported in ClinVar with a current expert-panel Benign classification, although older laboratory submissions include uncertain significance and likely benign assertions.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override)
Classification rationale
BS1BP1BP5BP6
Benign
BRCA1 c.2155A>G
BS1 + BP1 + BP5 + BP6
→
Benign
3
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗cspec ↗
4
spliceai ↗bayesdelrevelcspec ↗
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.15102e-05; MAF= 0.00415%, 67/1614060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000852583; MAF= 0.08526%, 64/75066 alleles, homozygotes = 0); grpmax FAF= 0.00068503.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.0823e-05; MAF= 0.00708%, 20/282394 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000803277; MAF= 0.08033%, 20/24898 alleles, homozygotes = 0); grpmax FAF= 0.00062195.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0042%
· 67 / 1,614,060
0 hom · FAF 0.069%
0 hom · FAF 0.069%
African/African American 64 / 75,066 |
0.085% |
Remaining individuals 3 / 62,506 |
0.0048% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.0071%
· 20 / 282,394
0 hom · FAF 0.062%
0 hom · FAF 0.062%
African/African American 20 / 24,898 |
0.08% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (7 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 37452)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.404. BayesDel score = -0.216062.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→BP5 supports · met
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
15385441 ↗
Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition.
CLINVAR
16267036 ↗
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.
CLINVAR
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
31911673 ↗
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR