Classification rationale

PVS1PM5PP4PP5 BS1 Pathogenic

BRCA2 c.5946del

NM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 resulting in a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay, in a gene where loss of function is an established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight.¹ ENIGMA Specifications Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 11, indicating additional pathogenic weight for a protein termination codon variant in an exon where other proven pathogenic PTC variants have been previously observed.² Clinical-history likelihood ratio analysis from Li et al. 2020 (PMID:31853058) yields an LR of 31.79 based on 149 carriers, exceeding the ENIGMA PP4_Strong threshold of ≥18.7:1. The personal and family cancer history profile of individuals carrying this variant is significantly enriched for breast and ovarian cancer compared to non-carriers.³ The variant is present in gnomAD population databases at low frequency in non-founder populations (grpmax FAF=5.39e-05 in v2.1, 2.154e-05 in v4.1), meeting ENIGMA BS1_Supporting (FAF >0.002% and ≤0.01%). The higher Ashkenazi Jewish allele frequency (0.589%) is attributable to a known founder effect and is excluded from BS1/BA1 assessment per ENIGMA non-founder population rules.⁴ This variant has been reported in ClinVar as Pathogenic by 67 clinical laboratories and by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 9325). The variant has been observed in multiple affected individuals across diverse populations and has been described as a recurrent pathogenic founder mutation.⁵ Under ENIGMA Table 3 combining rules, the combination of PVS1 (Very Strong) + PM5 (Strong) satisfies the Pathogenic classification threshold (1 Very Strong + ≥1 Strong). PP4 (Strong) provides additional corroborating evidence. BS1_Supporting does not alter the pathogenic classification.⁶

PVS1 + PM5 + PP4 + PP5 + BS1 → Pathogenic

1 vcep_specifications_table4_v1_2_2024_11_18cspec ↗pvs1_generic_framework ↗

2 vcep_specifications_table4_v1_2_2024_11_18cspec ↗

3 vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗

4 gnomad_v2 ↗gnomad_v4 ↗

5 clinvar ↗

6 cspec ↗

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

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 5 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 pathogenic

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

225 / 1,613,878

0.014%

Highest · Ashkenazi Jewish

0.53%

Homozygotes

0

grpmax FAF

0.0022%

Allele frequency by ancestry — gnomAD v4.1

observed in 3 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
Ashkenazi Jewish	158 / 29,596	0.53%	0
European (non-Finnish)	35 / 1,179,918	0.003%	0
African/African American	1 / 74,912	0.0013%	0
Admixed American	0 / 60,000	—	—
European (Finnish)	0 / 64,040	—	—
Amish	0 / 912	—	—
East Asian	0 / 44,854	—	—
Middle Eastern	0 / 6,082	—	—
South Asian	0 / 91,086	—	—

“

This variant is present in gnomAD v4.1 (AF= 0.000139416; MAF= 0.01394%, 225/1613878 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00533856; MAF= 0.53386%, 158/29596 alleles, homozygotes = 0); grpmax FAF= 2.154e-05.

Overall AF

78 / 282,088

0.028%

Highest · Ashkenazi Jewish

0.59%

Homozygotes

0

grpmax FAF

0.0054%

Allele frequency by ancestry — gnomAD v2.1

observed in 3 of 8 groups

Ancestry	Allele count	Frequency	Homozygotes
Ashkenazi Jewish	61 / 10,364	0.59%	0
Remaining individuals	3 / 7,180	0.042%	0
European (non-Finnish)	14 / 128,890	0.011%	0
African/African American	0 / 24,530	—	—
Admixed American	0 / 35,438	—	—
East Asian	0 / 19,952	—	—
European (Finnish)	0 / 25,124	—	—
South Asian	0 / 30,610	—	—

“

This variant is present in gnomAD v2.1 (AF= 0.000276509; MAF= 0.02765%, 78/282088 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00588576; MAF= 0.58858%, 61/10364 alleles, homozygotes = 0); grpmax FAF= 5.39e-05.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (67 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 9325)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66447676, n = 10 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · 71 PMIDs triaged · 8 high-priority

71papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

10570174 ↗ functional

Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.

BRCA2 mutations predispose carriers mainly to breast cancer. The vast majority of BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are crucial for BRCA2 function. A series of green fluorescent protein (GFP)-ta

BS3PM1PS3

10570174 ↗ functional

Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.

BRCA2 mutations predispose carriers mainly to breast cancer. The vast majority of BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are crucial for BRCA2 function. A series of green fluorescent protein (GFP)-ta

BS3PP5PS3PS4

11239455 ↗ functional

BRCA2 is required for homology-directed repair of chromosomal breaks.

The BRCA2 tumor suppressor has been implicated in the maintenance of chromosomal stability through a function in DNA repair. In this report, we examine human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination. Using the I-SceI endonuclease to introduce a double-strand break at a specific chromosomal locus, we find th

BS3PM1PS3

20878484 ↗ functional

A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.

Heterozygous germ line mutations in the Breast CAncer1 (BRCA1) and BRCA2 genes can lead to a high risk of breast and ovarian cancer, in addition to a significantly increased susceptibility of pancreatic, prostate and male breast cancer. The BRCA2 belongs to the tumor suppressor gene family and the protein encoded by this gene is involved in the repair of chromosomal damage, with an important role

BS3PM1PS3

22193408 ↗ functional

BRCA1 and BRCA2: different roles in a common pathway of genome protection.

The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous

BS3PM1PS3

24312913 ↗ functional

A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.

Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the popul

BS3PM1PS3

10417300 ↗ de novo

De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation.

PM6PP5PS2PS4

14559878 ↗ segregation

Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.

Fanconi anemia is an inherited disease characterized by bone marrow failure, congenital malformations, and predisposition to cancer. The breast cancer susceptibility gene BRCA2 was recently found to be associated with Fanconi anemia complementation group D1 (FA-D1). We examined four kindreds afflicted with Fanconi anemia for the presence of germline BRCA2 mutations. One kindred, of Ashkenazi Jewis

BS4PP1PP5PS4

11466700 ↗ background review

The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.

PP5PS4

28492532 ↗ background review

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

PS3PS4

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots