Classification rationale

PM2 BP7 VUS

BRIP1 c.3069C>T

The BRIP1 c.3069C>T (p.Leu1023=, p.L1023=) variant has been reported in ClinVar predominantly as likely benign or benign.¹ This variant is present at low frequency in gnomAD, with overall allele frequencies of 0.01061% in v2.1 and 0.00836% in v4.1, and highest observed South Asian frequencies of 0.06533% and 0.04721%, respectively; these values are below the default 0.1% PM2 threshold and below the 0.3% BS1 and 1% BA1 benign thresholds.² This synonymous variant is predicted to have no significant splice effect, with a SpliceAI maximum delta score of 0.01, which supports BP7 and argues against PP3.³

PM2 + BP7 → 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 · 2 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= 8.36413e-05; MAF= 0.00836%, 135/1614036 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000472133; MAF= 0.04721%, 43/91076 alleles, homozygotes = 0); grpmax FAF= 0.00035972.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000106072; MAF= 0.01061%, 30/282826 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000653253; MAF= 0.06533%, 20/30616 alleles, homozygotes = 0); grpmax FAF= 0.00043223.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0084% · 135 / 1,614,036
0 hom · FAF 0.036%

South Asian 43 / 91,076	0.047%
Remaining individuals 10 / 62,498	0.016%
European (non-Finnish) 81 / 1,180,014	0.0069%
African/African American 1 / 74,974	0.0013%

+ 6 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.011% · 30 / 282,826
0 hom · FAF 0.043%

South Asian 20 / 30,616	0.065%
Remaining individuals 1 / 7,222	0.014%
European (non-Finnish) 9 / 129,156	0.007%

+ 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 (8 clinical laboratories) and as Benign (3 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

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 ↗

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.

PMID PMID:34242744

PMID PMID:34242744 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP7 supports · met

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots