Classification rationale

BP4 VUS

BRIP1 c.1474-3T>C

The BRIP1 NM_032043.3:c.1474-3T>C (NP_114432.2:p.?) variant has been reported in ClinVar with predominantly benign and likely benign submissions, although uncertain significance submissions are also present.¹ This variant is present in population databases, including gnomAD v4.1 at an overall allele frequency of 0.01185% (191/1611312) and a highest observed South Asian frequency of 0.20440% (186/90996), with similar South Asian enrichment in gnomAD v2.1 at 0.16343% (50/30594); these values are above a 0.1% PM2 rarity threshold but below BA1 and BS1 thresholds.² In silico splice prediction does not support a significant splice effect, with a SpliceAI maximum delta score of 0.11, supporting BP4 and arguing against PP3.³

BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

Gene diagram · NM_032043.3 · variants mapped to exon structure

BRIP1 NM_032043.3

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= 0.000118537; MAF= 0.01185%, 191/1611312 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00204405; MAF= 0.20440%, 186/90996 alleles, homozygotes = 0); grpmax FAF= 0.0018038.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000207267; MAF= 0.02073%, 52/250884 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00163431; MAF= 0.16343%, 50/30594 alleles, homozygotes = 1); grpmax FAF= 0.00127276.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.012% · 191 / 1,611,312
0 hom · FAF 0.18%

South Asian 186 / 90,996	0.2%
Remaining individuals 4 / 62,392	0.0064%
East Asian 1 / 44,780	0.0022%

+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.021% · 52 / 250,884
1 hom · FAF 0.13%

South Asian 50 / 30,594	0.16% 1 hom
Remaining individuals 1 / 6,102	0.016%
European (non-Finnish) 1 / 113,498	0.00088%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (4 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).

SpliceAI ↗

Functional No data

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

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

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

COSMIC ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC