Classification rationale

BA1BS1BS3BP6 Benign

BRCA2 c.9976A>T

The BRCA2 c.9976A>T (p.Lys3326Ter, K3326*) variant has been observed in somatic cancers in COSMIC (18 occurrences) and has been reported in ClinVar with an expert-panel benign classification.¹ This variant is common in population databases, including gnomAD v2.1 with an overall allele frequency of 0.64680% and grpmax FAF of 0.849119%, and gnomAD v4.1 with an overall allele frequency of 0.79156%; these values are above the BRCA2 ENIGMA BA1 (>0.1%) and BS1 (>0.01%) thresholds.² Calibrated BRCA2 functional evidence supports a benign effect, with the expert specification assigning BS3 Strong to this exact variant based on protein function similar to benign controls.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07.⁴

BA1 + BS1 + BS3 + BP6 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_specifications_table9_v1_2_2024_11_18cspec ↗

4 spliceai ↗

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

BRCA2 NM_000059.4

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= 0.00791559; MAF= 0.79156%, 12777/1614156 alleles, homozygotes = 72) and has highest observed frequency in the Amish population (AF= 0.0351648; MAF= 3.51648%, 32/910 alleles, homozygotes = 2); grpmax FAF= 0.00883986.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00646801; MAF= 0.64680%, 1825/282158 alleles, homozygotes = 14) and has highest observed frequency in the European (Finnish) population (AF= 0.0109111; MAF= 1.09111%, 274/25112 alleles, homozygotes = 2); grpmax FAF= 0.00849119.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.79% · 12777 / 1,614,156
72 hom · FAF 0.88%

Amish 32 / 910	3.5% 2 hom
European (Finnish) 637 / 64,034	0.99% 5 hom
European (non-Finnish) 10600 / 1,180,014	0.9% 51 hom
Remaining individuals 451 / 62,504	0.72% 1 hom
Middle Eastern 42 / 6,062	0.69% 1 hom
South Asian 594 / 91,086	0.65% 11 hom
Ashkenazi Jewish 136 / 29,604	0.46%
Admixed American 197 / 60,008	0.33% 1 hom
African/African American 88 / 75,044	0.12%

+ 1 not observed (East Asian)

gnomAD v2.1

0.65% · 1825 / 282,158
14 hom · FAF 0.85%

European (Finnish) 274 / 25,112	1.1% 2 hom
European (non-Finnish) 1124 / 128,854	0.87% 6 hom
South Asian 212 / 30,594	0.69% 5 hom
Remaining individuals 46 / 7,190	0.64% 1 hom
Ashkenazi Jewish 42 / 10,358	0.41%
Admixed American 94 / 35,348	0.27%
African/African American 33 / 24,778	0.13%

+ 1 not observed (East Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (30 clinical laboratories) and as Likely benign (10 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

SpliceAI ↗

Functional Inconclusive

OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.

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; COSV66337127, n = 18 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID cspec

PMID cspec ↗

Found