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 ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

BRIP1 NM_032043.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 moderate Pathogenic

This variant is present at low frequency in population databases. The highest observed population frequency is 0.06533% in gnomAD v2.1 South Asian samples and 0.04721% in gnomAD v4.1 South Asian samples, both below the default 0.1% PM2 threshold, which supports PM2 under the generic fallback framework.

gnomAD v2.1 South Asian AF 0.000653253 (20/30616)gnomAD v4.1 South Asian AF 0.000472133 (43/91076)

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting Benign

This is a synonymous BRIP1 variant, p.(Leu1023=), and available splicing prediction does not indicate a meaningful splice effect. SpliceAI shows a maximum delta score of 0.01, supporting no significant splice impact, which meets BP7.

Synonymous protein consequence p.(Leu1023=)SpliceAI max delta score 0.01

spliceai ↗

Assessed · not applied · 6 not met · 13 not assessed

Pathogenic

PS1 No evidence was identified showing that a different nucleotide change producing the same amino acid alteration has been established as pathogenic, so PS1 was not assessed.

PS2 No confirmed de novo occurrence with verified parentage was identified, so PS2 was not assessed.

PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed.

PS4 No case-control or enrichment data were identified showing this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed.

PM1 Available evidence does not support location in a well-established mutational hotspot or critical functional domain without benign variation.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant for a recessive disorder, so PM3 was not assessed.

PM6 No assumed de novo occurrence was identified, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP3 Available computational evidence does not support a deleterious effect on splicing.

PP4 No phenotype or family history data sufficiently specific for a single genetic cause were identified for this variant, so PP4 was not assessed.

PP5 No reputable source classification supporting pathogenicity was identified.

Benign

BA1 Population frequency does not reach the standalone benign threshold.

BS1 Population frequency does not exceed the strong benign threshold.

BS2 No evidence was identified showing this variant in healthy adult individuals in a way that is sufficient to apply BS2, so BS2 was not assessed.

BS3 No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not assessed.

BS4 No segregation studies showing lack of segregation with disease were identified, so BS4 was not assessed.

BP2 No phase data showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant were identified, so BP2 was not assessed.

BP5 No evidence was identified for an alternate molecular basis explaining disease in carriers of this variant, so BP5 was not assessed.

BP6 Although ClinVar reports this variant as benign or likely benign, those submissions are listed with criteria provided rather than as unsupported assertions from a reputable source, so BP6 was not applied.

N/A · 7 PVS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

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.

Customizing local and systemic therapies for women with early breast cancer: the

PMID 34242744 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP7 supporting benign

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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