Classification rationale

PP3 Uncertain Significance

BRCA2 c.7961T>C

The BRCA2 c.7961T>C (p.Leu2654Pro) variant has been reported in ClinVar with an expert-panel classification of uncertain significance and mixed submitter assertions.¹ This variant is present at very low frequency in population databases, including 1/31,406 alleles in gnomAD v2.1 and 3/1,614,066 alleles in gnomAD v4.1, which argues against PM2 and does not reach BA1 or BS1 thresholds.² In the ENIGMA BRCA2 curated functional dataset, this variant has discordant calibrated assay results, so the available functional evidence does not support either PS3 or BS3.³ Computational evidence supports a damaging protein effect because the variant lies in the BRCA2 DNA-binding domain, BayesDel no-AF is 0.314702 above the PP3 threshold of 0.30, REVEL is 0.82, and SpliceAI predicts no significant splice effect with a max delta score of 0.02.⁴

PP3 → Uncertain Significance

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_specifications_table9_v1_2_2024_11_18PMID:29884841 ↗

4 cspec ↗bayesdelrevelspliceai ↗

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

BRCA2 NM_000059.3

Fetching transcript structure from UCSC…

Applied criteria · 1 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

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85866e-06; MAF= 0.00019%, 3/1614066 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= 4.43e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114784; MAF= 0.01148%, 1/8712 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,614,066
0 hom · FAF 0.00044%

African/African American 2 / 74,936	0.0027%
European (non-Finnish) 1 / 1,180,048	8.5e-05%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0032% · 1 / 31,406
0 hom

African/African American

1 / 8,712

0.011%

+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 52448)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.82. BayesDel score = 0.314702.

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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

29394989 ↗ Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. ONCOKB

35736817 ↗ Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay. ONCOKB

23108138 ↗ A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. 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

29884841 ↗ Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. CLINVAR

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