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

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

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 ↗

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 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

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

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