0%
complete
Final classification
Likely Benign
BS1BP4
BRIP1
c.3459T>C
p.Asp1153=
synonymous · exon 20
Gene context NCBI Gene ↗ OncoKB ↗

BRIP1 encodes a helicase enzyme that partners with the BRCA1 protein to repair double-strand breaks in DNA, a process essential for maintaining genome stability. Germline mutations in this gene predispose carriers to ovarian cancer, and inheriting two faulty copies causes Fanconi anemia complementation group J, a rare disorder of impaired DNA repair. BRIP1 acts as a tumor suppressor, so loss of its function raises cancer risk, particularly in the ovary.

This variant

BRIP1's tumor-suppressor role in BRCA1-partnered DNA repair means loss-of-function variants raise ovarian-cancer risk. This synonymous variant (p.Asp1153=) shows no predicted splice effect and is carried at 1.62% in the gnomAD Middle Eastern population, indicating BRIP1 function is not impaired. The Likely Benign classification therefore carries no evidence of increased cancer risk.

Transcript
NM_032043.3
HGVS · transcript:coding
NM_032043.3:c.3459T>C
GRCh38
chr17:61683587 A>G
GRCh37
chr17:59760948 A>G
No BRIP1 VCEP or gene-specific framework was available, so generic ACMG/AMP 2015 rules were applied; BS1 (Strong) plus BP4 (Supporting) yields Likely Benign.
Classification rationale
BS1BP4 Likely Benign
BRIP1 c.3459T>C synonymous · exon 20

BS1 (Strong): 1.62% allele frequency in gnomAD v4.1 Middle Eastern exceeds the >0.3% threshold for benign population frequency. BP4 (Supporting): SpliceAI maximum delta 0.004 is below the 0.1 threshold, indicating no predicted splice impact. Final: Likely Benign by generic ACMG/AMP 2015 combination rules (BS1 Strong + BP4 Supporting).

BS1 + BP4 → Likely Benign
Gene diagram · NM_032043.3 · variants mapped to exon structure
BRIP1 NM_032043.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 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
BS1 strong Benign
Met (Strong): 1.62% frequency in gnomAD v4.1 Middle Eastern exceeds the >0.3% benign-population threshold.
gnomAD v4.1 Middle Eastern group: 98/6060 alleles, AF 0.0161716 (1.61716%), one homozygote; joint grpmax FAF 0.0135815 (1.35815%).gnomAD v4.1 overall AF is 0.000673468 (0.06735%); gnomAD v2.1 overall AF is 0.000756801 (0.07568%); gnomAD-Canada AF is 0.00146612 (0.14661%). These pooled values are lower because of ancestry mixing and do not negate the much higher Middle Eastern subgroup frequency.Local non-VCEP operating convention for BS1 is AF >0.3%; the Middle Eastern gnomAD v4.1 frequency exceeds this threshold by more than fivefold.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 supporting Benign
Met (Supporting): SpliceAI maximum delta 0.004 is below the 0.1 no-splice-impact threshold.
SpliceAI reports DS_AG 0.001, DS_AL 0.000, DS_DG 0.004, and DS_DL 0.004; maximum delta score is 0.004 for NM_032043.3:c.3459T>C.The retrieved generic ACMG/AMP fallback designates SpliceAI as the single computational mechanism for synonymous variants and assigns BP4 supporting when maximum delta score is less than 0.1; the observed maximum delta score is 0.004.No BRIP1 VCEP specification, gene-specific PP3/BP4 lookup, or pre-assigned computational code was retrieved.
spliceai ↗
Assessed · not applied · 5 not met · 13 not assessed
Pathogenic
PS2 Not assessed: no confirmed de novo occurrence with informative parental testing was documented.
PS3 Not assessed: no validated functional assay evidence reporting this variant was identified.
PS4 Not assessed: no case-control data, affected counts, or enrichment statistics for this variant were available.
PM2 Not met: the highest relevant population frequency is 1.62% (gnomAD v4.1 Middle Eastern), exceeding the <0.1% PM2 threshold.
PM3 Not assessed: no second pathogenic allele, phasing result, or in-trans evidence was documented.
PM6 Not assessed: no evidence of presumed de novo occurrence without confirmed parentage was documented.
PP1 Not assessed: no affected relatives, informative meioses, or segregation data were documented.
PP3 Not met: SpliceAI maximum delta 0.004 does not meet the splice-impact threshold.
PP4 Not assessed: no phenotype, age-of-onset, or family-history information for the tested individual was supplied.
PP5 Not met: ClinVar record 136580 has zero expert-panel submissions, so no expert-panel pathogenic assertion exists.
Benign
BA1 Not met: highest gnomAD v4.1 ancestry frequency is 1.62% (Middle Eastern), below the >5% stand-alone threshold.
BS2 Not assessed: gnomAD reports one homozygote, but aggregate data do not establish a clinically unaffected adult of relevant age.
BS3 Not assessed: no validated functional assay demonstrating a benign effect for this variant was identified.
BS4 Not assessed: no unaffected tested relatives were documented to evaluate non-segregation.
BP2 Not assessed: no data document the variant in cis with a pathogenic allele.
BP5 Not assessed: no phenotype information or alternate molecular diagnosis was available.
BP6 Not met: ClinVar record 136580 has zero expert-panel submissions, so no expert-panel benign assertion exists.
BP7 Not assessed: the no-splice-impact prediction was already counted under BP4, and no conservation evidence was available.
N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000673468; MAF= 0.06735%, 1086/1612548 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.0161716; MAF= 1.61716%, 98/6060 alleles, homozygotes = 1); grpmax FAF= 0.0135815.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000756801; MAF= 0.07568%, 213/281448 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00180606; MAF= 0.18061%, 13/7198 alleles, homozygotes = 0); grpmax FAF= 0.00089984.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014661164205039096, 27/18416 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.067% · 1086 / 1,612,548
1 hom · FAF 1.4%
Middle Eastern
98 / 6,060
1.6%
1 hom
Remaining individuals
76 / 62,480
0.12%
Admixed American
67 / 59,990
0.11%
Ashkenazi Jewish
30 / 29,596
0.1%
European (non-Finnish)
733 / 1,179,930
0.062%
South Asian
56 / 91,042
0.062%
African/African American
26 / 75,000
0.035%
+ 3 not observed (European (Finnish), Amish, East Asian)
gnomAD v2.1
0.076% · 213 / 281,448
0 hom · FAF 0.09%
Remaining individuals
13 / 7,198
0.18%
Ashkenazi Jewish
14 / 10,366
0.14%
Admixed American
43 / 35,346
0.12%
European (non-Finnish)
126 / 128,912
0.098%
South Asian
13 / 30,568
0.043%
African/African American
4 / 24,908
0.016%
+ 2 not observed (East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.15% · 27 / 18,416
0 hom · FAF 0.13%
Middle Eastern
1 / 144
0.69%
Remaining individuals
5 / 1,138
0.44%
African/African American
4 / 1,020
0.39%
Ashkenazi Jewish
2 / 832
0.24%
South Asian
3 / 1,362
0.22%
Latino/Admixed American
1 / 838
0.12%
European (non-Finnish)
11 / 11,736
0.094%
+ 2 not observed (East Asian, European (Finnish))
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (12 clinical laboratories) and as Benign (6 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 136580)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 8 PMIDs not cited in assessment
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
26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR
26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR
34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR
42258614 ↗ ATM-Related Cancer Predisposition. CLINVAR
22964825 ↗ Screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR