Classification rationale

BA1BS1BP4BP6 Benign

BRCA2 c.68-7del

The BRCA2 c.68-7del (p.?) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 expert panel, although some ClinVar submissions remain uncertain significance.¹ This variant is present in gnomAD, and in gnomAD v2.1 the grpmax filter allele frequency is 0.00155833, which is above the ENIGMA BRCA2 BA1 threshold of 0.001 and the BS1 strong threshold of 0.0001.² Computational splicing evidence does not support a deleterious effect because SpliceAI predicts a maximum delta score of 0.04, which is below the BRCA2 BP4 threshold of 0.1 and below the PP3 threshold of 0.2.³

BA1 + BS1 + BP4 + BP6 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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_000059.3 · variants mapped to exon structure

BRCA2 NM_000059.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 13 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant is too common for a pathogenic BRCA2 variant under the ENIGMA frequency framework. In gnomAD v2.1, the grpmax filter allele frequency is 0.00155833, which is above the BA1 threshold of 0.001 in a non-founder population.

gnomAD v2.1 grpmax FAF = 0.00155833.BA1 threshold in BRCA2 ENIGMA specification is FAF >0.001.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 strong Benign

This variant exceeds the BRCA2 BS1 frequency threshold. In gnomAD v2.1, the grpmax filter allele frequency is 0.00155833, which is above the BS1 strong threshold of 0.0001.

gnomAD v2.1 grpmax FAF = 0.00155833.BS1 strong threshold in BRCA2 ENIGMA specification is FAF >0.0001.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 supporting Benign

This intronic variant is outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.04, which is below the BRCA2 BP4 threshold of 0.1. This supports BP4.

Intronic variant at c.68-7 is outside the canonical +/-12 splice positions.SpliceAI max delta score = 0.04.

spliceai ↗cspec ↗

BP6 supporting Benign

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.

BP6 is marked not applicable in the BRCA2 specification.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 3 not met · 10 not assessed

Pathogenic

PVS1 BRCA2 loss of function is an established disease mechanism in this framework, but this intronic c.68-7del variant is not a canonical +/-1,2 splice-site change and no RNA study showing an abnormal transcript was identified.

PS1 PS1 can be used for intronic or exonic variants with the same predicted splicing effect as a previously classified pathogenic or likely pathogenic variant, but no verified comparator with the same predicted splice outcome was identified here.

PS3 No published functional study showing a damaging effect for BRCA2 c.68-7del was identified, and this variant was not found in the curated ENIGMA functional assay table reviewed for PS3/BS3 use.

PS4 No case-control or quantitative prevalence data showing a significant enrichment of this variant in affected individuals versus controls were identified, so PS4 is not established.

PM2 This variant is present in population databases and therefore is not absent from controls.

PM3 No evidence was identified that this variant was observed in trans with another BRCA2 pathogenic or likely pathogenic variant in an individual with BRCA2-related Fanconi anemia, so PM3 cannot be applied.

PP1 No quantitative cosegregation data were identified for this variant, so PP1 cannot be applied.

PP3 SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.04, which is below the BRCA2 PP3 threshold of 0.2.

PP4 No exact variant-level clinical-history likelihood ratio was identified for BRCA2 c.68-7del in the reviewed ENIGMA clinical-history materials, so PP4 was not established.

Benign

BS2 No point-based evidence from individuals lacking features of BRCA2-related Fanconi anemia was identified to support BS2 under the BRCA2 specification.

BS3 No calibrated functional study showing no damaging effect for BRCA2 c.68-7del was identified, and this variant was not found in the curated ENIGMA functional assay table for BS3 use.

BS4 No quantitative nonsegregation data were identified for this variant, so BS4 cannot be applied.

BP5 No exact variant-level clinical-history likelihood ratio was identified for BRCA2 c.68-7del in the reviewed ENIGMA clinical-history materials, so BP5 was not established.

N/A · 11 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000261677; MAF= 0.02617%, 409/1562996 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000730943; MAF= 0.07309%, 42/57460 alleles, homozygotes = 0); grpmax FAF= 0.00055521.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000846545; MAF= 0.08465%, 198/233892 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00201734; MAF= 0.20173%, 47/23298 alleles, homozygotes = 0); grpmax FAF= 0.00155833.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.026% · 409 / 1,562,996
0 hom · FAF 0.056%

Admixed American 42 / 57,460	0.073%
South Asian 52 / 87,242	0.06%
Remaining individuals 15 / 60,324	0.025%
European (Finnish) 15 / 61,188	0.025%
European (non-Finnish) 266 / 1,144,988	0.023%
Ashkenazi Jewish 6 / 28,514	0.021%
Middle Eastern 1 / 5,534	0.018%
African/African American 11 / 73,298	0.015%
East Asian 1 / 43,540	0.0023%

+ 1 not observed (Amish)

gnomAD v2.1

0.085% · 198 / 233,892
0 hom · FAF 0.16%

South Asian 47 / 23,298	0.2%
Admixed American 30 / 27,606	0.11%
Remaining individuals 6 / 5,910	0.1%
Ashkenazi Jewish 8 / 8,418	0.095%
European (non-Finnish) 76 / 108,796	0.07%
East Asian 11 / 16,654	0.066%
African/African American 12 / 21,740	0.055%
European (Finnish) 8 / 21,470	0.037%

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 52188)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV66448762, n = 8 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Triaged references · 9 PMIDs not cited in assessment

10451700 ↗ A somatic BRCA2 mutation in RER+ endometrial carcinomas that specifically deletes the amino-terminal transactivation domain. 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

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

17333343 ↗ BRCA1 and BRCA2 status in a Central Sudanese series of breast cancer patients: interactions with genetic, ethnic and reproductive factors. CLINVAR

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

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

Check your email

Reset your password

Enter an access code

Your allowance