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 ↗

Gene diagram · NM_000059.3 · variants mapped to exon structure

BRCA2 NM_000059.3

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= 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 ↗

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 vcep_specifications_v1_2_2024_11_18

PMID vcep_specifications_v1_2_2024_11_18 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BA1 supports · met →BP4 supports · met →BP6 supports · met →BS1 supports · met

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