Classification rationale

BS1BS4BP1 Likely Benign

BRCA2 c.3073A>G missense · exon 11

BP1 (Strong): missense change outside both clinically important BRCA2 domains with no predicted splice impact (SpliceAI max delta 0.00). BS1 (Supporting): gnomAD allele frequency 5.795e-05 in v4.1 falls within the 0.00002-0.0001 supporting range. BS4 (Supporting): ENIGMA segregation likelihood ratio 0.445 meets the <=0.48 threshold, favoring lack of cosegregation. Overall Likely Benign: BP1_Strong plus BS1 and BS4 Supporting satisfies the one-Strong-plus-one-Supporting benign combination rule (ENIGMA score -6).

BS1 + BS4 + BP1 → Likely Benign

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 17 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 · 3

Strength Supporting Moderate Strong Very strong

BS1 supporting Benign

Met (Supporting): the highest gnomAD allele frequency, 5.795e-05, falls within the ENIGMA supporting range of 0.00002 to 0.0001.

The applicable ClinGen ENIGMA BRCA1/2 specification v1.2 defines BS1 Supporting as maximum non-founder gnomAD FAF above 0.002% and at or below 0.01% (0.00002 < FAF <= 0.0001).gnomAD v2.1 reports maximum group FAF 5.405e-05 (0.005405%), with 12/250060 total alleles and zero homozygotes; gnomAD v4.1 reports maximum group FAF 5.795e-05 (0.005795%), with 86/1613120 total alleles and zero homozygotes.The gnomAD v2.1 and v4.1 FAF values are above the Supporting lower threshold and below the Strong threshold of FAF >0.0001; the small-subgroup raw AF values are not substituted for FAF.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS4 supporting Benign

Met (Supporting): segregation likelihood ratio 0.445 meets the <=0.48 supporting threshold for lack of segregation.

ENIGMA BRCA2 v1.2 specifies BS4 Supporting for quantitative lack-of-segregation LR <=0.48, Moderate for LR <=0.23, Strong for LR <=0.05, and Very Strong for LR <=0.00285.The exact-variant ENIGMA multifactorial row for BRCA2 c.3073A>G (p.Lys1025Glu) reports Segregation LR = 0.445, meeting the Supporting threshold.The variant-specific paper extraction for PMID:32599251 reports one observation of rs80358550 (p.K1025E) but no segregation analysis; it therefore does not independently establish BS4.

cspec ↗

BP1 strong Benign

Met (Strong): missense change outside both clinically important BRCA2 domains with no predicted splice impact (SpliceAI delta 0.00).

ENIGMA BRCA2 v1.2 specifies BP1_Strong for silent, missense, or in-frame insertion/deletion/delins variants outside a clinically important domain when SpliceAI is <=0.1.The variant is NP_000050.3:p.(Lys1025Glu), and Lys1025 is outside the ENIGMA domains aa 10-40 and aa 2481-3186.SpliceAI maximum delta score is 0.00, below the ENIGMA threshold of 0.1.

cspec ↗spliceai ↗

Assessed · not applied · 11 not met · 6 not assessed

Pathogenic

PVS1 Not met: c.3073A>G is a missense (p.Lys1025Glu), not a null variant, and SpliceAI max delta 0.00 indicates no damaging transcript effect.

PS1 Not assessed: no previously classified pathogenic BRCA2 variant producing the same amino-acid change (p.Lys1025Glu) was documented.

PS3 Not assessed: no calibrated functional assay evidence exists, and this variant has no entry in the ENIGMA Table 9 functional data.

PS4 Not met: no case-control enrichment was identified, and the ENIGMA multifactorial record lacks a case-control LR for this exact variant.

PM2 Not met: the variant is observed in gnomAD non-cancer controls (86/1,613,120 alleles in v4.1), so it is not absent as required.

PM3 Not assessed: no Fanconi anemia phenotype or second pathogenic BRCA2 variant is documented, so PM3 could not be applied.

PP1 Not met: segregation likelihood ratio 0.445 is below the >=2.08 supporting threshold and favors lack of cosegregation.

PP3 Not met: p.Lys1025Glu is outside the clinically important BRCA2 domains, and SpliceAI max delta 0.00 is below the >=0.20 threshold.

PP4 Not met: the ENIGMA multifactorial likelihood ratio of 2.035 is below the >=2.08 PP4 supporting threshold.

PP5 Not met: ClinVar has no expert-panel Pathogenic or Likely pathogenic submission for this exact variant.

Benign

BA1 Not met: maximum allele frequency 5.795e-05 in gnomAD is below the BA1 threshold of >0.001.

BS2 Not assessed: gnomAD provides no adult health status, age, or penetrance follow-up data needed to assess BS2.

BS3 Not assessed: no calibrated functional assay showing a benign effect exists, and this variant is absent from ENIGMA Table 9.

BP4 Not met: BP4 requires location inside a clinically important domain, and p.Lys1025Glu is outside both.

BP5 Not met: the ENIGMA multifactorial likelihood ratio of 2.035 is above the <=0.48 BP5 supporting threshold.

BP6 Not met: ClinVar has no expert-panel Benign or Likely benign submission for this exact variant.

BP7 Not assessed: no variant-specific RNA splicing assay is available, and BP7 supporting applies only to silent variants.

N/A · 8 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.33128e-05; MAF= 0.00533%, 86/1613120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.03719e-05; MAF= 0.00704%, 83/1179448 alleles, homozygotes = 0); grpmax FAF= 5.795e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.79885e-05; MAF= 0.00480%, 12/250060 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.72298e-05; MAF= 0.00972%, 11/113134 alleles, homozygotes = 0); grpmax FAF= 5.405e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0053% · 86 / 1,613,120
0 hom · FAF 0.0058%

European (non-Finnish) 83 / 1,179,448	0.007%
Admixed American 2 / 59,896	0.0033%
African/African American 1 / 75,022	0.0013%

+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0048% · 12 / 250,060
0 hom · FAF 0.0054%

European (non-Finnish) 11 / 113,134	0.0097%
Admixed American 1 / 34,346	0.0029%

+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

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 Likely benign (6 clinical laboratories) and as Uncertain significance (5 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 51393)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.375. BayesDel score = -0.185286.

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. BRCA2, 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 · 9 PMIDs not cited in assessment

22476429 ↗ Mutation screening of RAD51C in high-risk breast and ovarian cancer families. CLINVAR

25348012 ↗ Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. 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

31131967 ↗ Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. CLINVAR

31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". CLINVAR

32123317 ↗ Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. CLINVAR

32599251 ↗ Characterization and in silico analyses of the BRCA1/2 variants identified in individuals with personal and/or family history of BRCA-related cancers. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR