Back
NM_007294.4:c.2597G>A
p.Arg866His · BRCA1
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.2 · v1.2
0%
complete
Final classification
VUS
BP6
BRCA1
c.2597G>A
p.Arg866His
missense · exon 10
Gene context NCBI Gene ↗ OncoKB ↗

BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.

This variant

BRCA1 variants that impair DNA double-strand-break repair raise the risk of hereditary breast and ovarian cancer. This variant is currently a VUS: the available evidence does not establish whether c.2597G>A alters BRCA1 function, so it cannot yet be used to confirm or exclude hereditary cancer risk.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.2597G>A
GRCh38
chr17:43092934 C>T
GRCh37
chr17:41244951 C>T
VUS: the single supporting-benign BP6 (ENIGMA expert panel: Benign) gives -1 point, which falls within the ENIGMA VUS range of -1 to 5.
Classification rationale
BP6 VUS
BRCA1 c.2597G>A missense · exon 10

BP6 (Supporting benign): the ENIGMA expert panel classified this variant as Benign. Overall: VUS - a lone supporting-benign criterion satisfies no ENIGMA benign-combination rule, and the -1 point score lands in the VUS range (-1 to 5).

BP6 → VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 27 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
BP6 supporting review Benign
Met (supporting benign): the ENIGMA expert panel classified this variant as Benign.
ClinVar expert panel classification
clinvar ↗
Assessed · not applied · 0 not met · 27 not assessed
Pathogenic
PVS1 Not assessed: insufficient evidence was available to determine whether this variant causes complete loss of BRCA1 function.
PS1 Not assessed: insufficient evidence was available to compare this change with pathogenic variants reported at the same residue.
PS2 Not assessed: insufficient evidence of a confirmed de novo occurrence was available.
PS3 Not assessed: insufficient functional-study evidence of a damaging effect was available.
PS4 Not assessed: insufficient evidence from affected individuals was available.
PM1 Not assessed: insufficient evidence was available to determine whether the variant falls in a known mutational hotspot.
PM2 Not assessed: population frequency data were insufficient to evaluate rarity.
PM3 Not assessed: insufficient evidence was available to evaluate biallelic inheritance.
PM4 Not assessed: insufficient evidence was available to evaluate a resulting change in protein length.
PM5 Not assessed: insufficient evidence was available to compare this change with pathogenic missense variants at the same codon.
PM6 Not assessed: insufficient evidence of a de novo occurrence without confirmed parentage was available.
PP1 Not assessed: insufficient familial segregation data was available.
PP2 Not assessed: insufficient evidence was available to evaluate the gene's missense-variant profile.
PP3 Not assessed: insufficient computational evidence of a damaging effect was available.
PP4 Not assessed: insufficient phenotype-specific data was available.
PP5 Not assessed: insufficient evidence from a reputable pathogenic source was available.
Benign
BA1 Not assessed: population frequency data were insufficient to apply the benign frequency threshold.
BS1 Not assessed: population frequency data were insufficient to support a benign frequency.
BS2 Not assessed: insufficient observations of the variant in healthy individuals were available.
BS3 Not assessed: insufficient functional-study evidence of no effect on function was available.
BS4 Not assessed: insufficient evidence of the variant failing to segregate with disease was available.
BP1 Not assessed: insufficient evidence was available to evaluate whether missense is a disease mechanism in this gene.
BP2 Not assessed: insufficient evidence was available to evaluate the variant alongside a pathogenic allele in trans.
BP3 Not assessed: insufficient evidence was available to evaluate an in-frame change in a low-complexity region.
BP4 Not assessed: insufficient computational evidence of no damaging effect was available.
BP5 Not assessed: insufficient evidence of an alternate cause of disease in this individual was available.
BP7 Not assessed: insufficient evidence was available to evaluate the splice impact of this change.
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.98312e-05; MAF= 0.00198%, 32/1613622 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66894e-05; MAF= 0.00267%, 2/74936 alleles, homozygotes = 0); grpmax FAF= 1.645e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.7702e-05; MAF= 0.00177%, 5/282454 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00673e-05; MAF= 0.00401%, 1/24958 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.002% · 32 / 1,613,622
0 hom · FAF 0.0016%
African/African American
2 / 74,936
0.0027%
European (non-Finnish)
28 / 1,179,948
0.0024%
South Asian
2 / 91,076
0.0022%
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0018% · 5 / 282,454
0 hom · FAF 0.00029%
African/African American
1 / 24,958
0.004%
South Asian
1 / 30,596
0.0033%
European (non-Finnish)
3 / 129,048
0.0023%
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 54613)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.735. BayesDel score = 0.145553.
SpliceAI ↗
Functional / OncoKB screenshot
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 8 PMIDs not cited in assessment
23867111 ↗ A high-throughput functional complementation assay for classification of BRCA1 missense variants. ONCOKB
38242199 ↗ Variant of uncertain significance Arg866Cys enhances disorderedness of h-BRCA1 (759-1064) region. ONCOKB
12938098 ↗ Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families in Southern Germany. CLINVAR
15385441 ↗ Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. CLINVAR
18273839 ↗ Unclassified variants identified in BRCA1 exon 11: Consequences on splicing. 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
28993434 ↗ Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. CLINVAR
31112341 ↗ BRCA1- and BRCA2-specific in silico tools for variant interpretation in the CAGI 5 ENIGMA challenge. CLINVAR