No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.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.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Met (Strong): 1.62% frequency in gnomAD v4.1 Middle Eastern exceeds the >0.3% benign-population threshold.
Met (Supporting): SpliceAI maximum delta 0.004 is below the 0.1 no-splice-impact threshold.
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.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1,086 / 1,612,548 alleles. Recorded AF 0.000673468. Recorded homozygote count 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.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014661164205039096, 27/18416 alleles, homozygotes = 0).
Recorded SpliceAI maximum delta score: 0.004. Refer to the recorded PP3/BP4 rationale for interpretation.
12 Likely benign · 6 Benign · 1 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
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).
No criteria match.
BS1 is met at strong benign strength. The variant reaches 1.61716% in the gnomAD v4.1 Middle Eastern ancestry group (98/6060 alleles; joint grpmax FAF 1.35815%), substantially exceeding the local non-VCEP operating threshold of >0.3% and far exceeding a plausible frequency for a rare pathogenic BRIP1 allele. The same variant is observed at 0.06735% overall in gnomAD v4.1, 0.07568% in gnomAD v2.1, and 0.14661% in gnomAD-Canada; the ancestry-specific enrichment is the decisive observation and should not be obscured by the lower pooled frequency.
generic_acmg_2015_bs1; local non-VCEP operating threshold AF >0.3%
BRIP1 has no governing VCEP or gene-specific specification in the case materials. For this synonymous variant, the applicable generic non-missense splice-impact rule is met: SpliceAI maximum delta score is 0.004, below the BP4 threshold of 0.1.
Generic ACMG/AMP fallback: for a synonymous non-missense variant, assess the splice-impact path with SpliceAI only; BP4 supporting requires maximum delta score <0.1.
PM2 is not met. Although the pooled frequency is low (0.06735% in gnomAD v4.1 and 0.07568% in gnomAD v2.1), PM2 rarity must account for ancestry-specific frequency. The variant occurs at 1.61716% in the gnomAD v4.1 Middle Eastern group (joint grpmax FAF 1.35815%) and is present in gnomAD-Canada at 0.14661%, exceeding the local non-VCEP PM2 operating threshold of <0.1% when the highest relevant population frequency is considered. The variant is therefore not sufficiently rare in controls for PM2.
generic_acmg_2015_pm2; local non-VCEP rarity threshold AF <0.1% applied to the highest relevant ancestry frequency
BRIP1 has no governing VCEP or gene-specific specification in the case materials. The synonymous variant's SpliceAI maximum delta score is 0.004, which does not meet the generic non-missense splice-impact PP3 threshold.
Generic ACMG/AMP fallback: for a synonymous non-missense variant, assess the splice-impact path with SpliceAI only; PP3 supporting requires maximum delta score >0.2.
ClinVar record 136580 exactly matches NM_032043.3:c.3459T>C (p.Asp1153=), but its submission audit identifies zero expert-panel submissions. Therefore, no exact-variant expert-panel Pathogenic/Likely pathogenic assertion is available and PP5 is not met.
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
BA1 is not met under the generic ACMG/AMP framework. The highest observed gnomAD v4.1 ancestry frequency is 0.0161716 (1.61716%) in the Middle Eastern group, with joint grpmax FAF 0.0135815 (1.35815%); these are below the generic stand-alone BA1 threshold of >5%. The variant is also present at 0.07568% in gnomAD v2.1 and 0.06735% in gnomAD v4.1 overall, so it is not population-absent.
generic_acmg_2015_ba1
ClinVar record 136580 exactly matches NM_032043.3:c.3459T>C (p.Asp1153=), but its submission audit identifies zero expert-panel submissions. Thus, despite ordinary laboratory Benign/Likely benign submissions, no exact-variant expert-panel Benign/Likely benign assertion is available and BP6 is not met.
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.
No case-level evidence documenting a confirmed de novo occurrence in the proband, including informative parental testing, is present in the evidence bundle. The variant's presence in population databases and ClinVar submissions does not establish de novo status.
Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected individual with confirmed maternity and paternity; strength depends on the quality and number of de novo observations and phenotype consistency.
No variant-specific validated functional assay evidence was identified for BRIP1 NM_032043.3:c.3459T>C (p.Asp1153=). The available functional-themed publications are general ACMG/AMP guidance or a general scoring-system description and do not report this variant or an assay result for it. Therefore PS3 cannot be assigned.
Generic ACMG/AMP PS3: use only well-established functional studies supportive of a damaging effect; no strength assignment is possible without variant-specific validated assay evidence.
No applicable BRIP1 VCEP specification was retrieved. Under the generic ACMG/AMP fallback, there are no exact-variant case-control data, affected-case counts, control counts, or enrichment statistics for NM_032043.3:c.3459T>C (p.Asp1153=); PS4 cannot be assessed.
Generic ACMG/AMP fallback: PS4 requires statistically increased prevalence in affected individuals versus controls.
No applicable BRIP1 VCEP/CSPEC specification was retrieved, so generic ACMG/AMP criteria are used. The case bundle contains no affected-proband observation, second pathogenic or likely pathogenic BRIP1 allele, or phasing/inheritance result demonstrating that NM_032043.3:c.3459T>C is in trans with a pathogenic variant. The available case data therefore do not permit assessment of PM3; the variant's synonymous annotation and population observations do not establish PM3.
Generic ACMG/AMP PM3: pathogenic variant detected in trans with a pathogenic variant in an affected individual with a recessive disorder; phase and phenotype must be established.
No case-level or published evidence documents the variant as presumed de novo without confirmed maternity and paternity. No informative family or meiosis data are available to support PM6.
Generic ACMG/AMP PM6 is used for a presumed de novo variant in an affected individual when maternity and paternity are not confirmed; it is weaker than PS2 and requires credible clinical and inheritance documentation.
No affected relatives carrying the variant, informative meioses, or family segregation data are documented. Phenotype and inheritance information are insufficient to evaluate co-segregation.
Generic ACMG/AMP PP1 supports co-segregation of a variant with disease in multiple affected family members; the evidence should be based on informative meioses and phenotype consistency, with strength adjusted for the amount and informativeness of segregation.
No applicable BRIP1 VCEP specification was retrieved. No individual-level phenotype, age of onset, family history, or phenotype specificity information is supplied for the tested individual, so PP4 cannot be evaluated.
Generic ACMG/AMP fallback: PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD v4.1 reports one homozygote, but aggregate gnomAD data do not establish that the individual was a clinically unaffected adult, the relevant age, or the absence of BRIP1-related disease. In addition, BRIP1 cancer predisposition is reduced penetrance/age-dependent rather than a fully penetrant early-onset dominant disorder, so a homozygote count alone cannot satisfy the healthy-adult BS2 requirement.
generic_acmg_2015_bs2
No variant-specific validated functional assay demonstrating a benign effect was identified for BRIP1 NM_032043.3:c.3459T>C (p.Asp1153=). The available functional-themed publications do not report this variant or a benign assay result, and the absence of a splice prediction is not equivalent to a validated benign functional study. Therefore BS3 cannot be assigned.
Generic ACMG/AMP BS3: use only well-established functional studies showing no damaging effect on protein function or splicing; no strength assignment is possible without variant-specific validated assay evidence.
No informative unaffected relatives who were tested and found not to carry the variant are documented. Therefore, non-segregation cannot be assessed.
Generic ACMG/AMP BS4 supports lack of segregation in an affected family, or presence of the variant in unaffected relatives when they are informative for the disease; interpretation requires adequate phenotype, age, penetrance, and genotype information.
No applicable BRIP1 VCEP/CSPEC specification was retrieved, so generic ACMG/AMP criteria are used. The case bundle contains no affected-proband observation showing the variant in cis with a pathogenic variant, no phase result, and no documented pathogenic or likely pathogenic allele with which to evaluate co-occurrence. Accordingly, BP2 cannot be assessed from the available evidence.
Generic ACMG/AMP BP2: observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or in cis with a pathogenic variant for a recessive disorder, when the relevant phenotype and phase are established.
No applicable BRIP1 VCEP specification was retrieved. The evidence bundle supplies no phenotype information and no documented alternate molecular diagnosis that fully explains a reported phenotype; BP5 cannot be assessed.
Generic ACMG/AMP fallback: BP5 requires an alternate molecular basis for disease in an individual with the variant.
The variant is synonymous, but BP7 is not applied because the available no-splice-impact prediction has already been used for BP4 and cannot be double-counted across these criteria. In addition, the case bundle contains no nucleotide-conservation evidence needed for a separate BP7 assessment.
Generic ACMG/AMP fallback; do not double-count the same no-splice-impact computational prediction across BP4 and BP7.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_032043.3:c.3459T>C in BRIP1 is a synonymous (silent) substitution predicted to produce NP_114432.2:p.(Asp1153=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
Every interpreted variant in BRIP1, mapped onto the exon structure of NM_032043.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Middle Eastern98 / 6,060 | 0.0161 hom |
| Remaining individuals76 / 62,480 | 0.0012 |
| Admixed American67 / 59,990 | 0.0011 |
| Ashkenazi Jewish30 / 29,596 | 0.001 |
| European (non-Finnish)733 / 1,179,930 | 0.00062 |
| South Asian56 / 91,042 | 0.00062 |
| African/African American26 / 75,000 | 0.00035 |
| Remaining individuals13 / 7,198 | 0.0018 |
| Ashkenazi Jewish14 / 10,366 | 0.0014 |
| Admixed American43 / 35,346 | 0.0012 |
| European (non-Finnish)126 / 128,912 | 0.00098 |
| South Asian13 / 30,568 | 0.00043 |
| African/African American4 / 24,908 | 0.00016 |
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.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014661164205039096, 27/18416 alleles, homozygotes = 0).
BRIP1 has no governing VCEP or gene-specific specification in the case materials. For this synonymous variant, the applicable generic non-missense splice-impact rule is met: SpliceAI maximum delta score is 0.004, below the BP4 threshold of 0.1.
Generic ACMG/AMP fallback: for a synonymous non-missense variant, assess the splice-impact path with SpliceAI only; BP4 supporting requires maximum delta score <0.1.
BRIP1 has no governing VCEP or gene-specific specification in the case materials. The synonymous variant's SpliceAI maximum delta score is 0.004, which does not meet the generic non-missense splice-impact PP3 threshold.
Generic ACMG/AMP fallback: for a synonymous non-missense variant, assess the splice-impact path with SpliceAI only; PP3 supporting requires maximum delta score >0.2.
The variant is synonymous, but BP7 is not applied because the available no-splice-impact prediction has already been used for BP4 and cannot be double-counted across these criteria. In addition, the case bundle contains no nucleotide-conservation evidence needed for a separate BP7 assessment.
Generic ACMG/AMP fallback; do not double-count the same no-splice-impact computational prediction across BP4 and BP7.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Clinical reports should include sequence reference(s) to ensure unambiguous naming of the variant at the DNA level as well as provide coding and protein nomenclature to assist in functional interpretations (e.g., “g.” for genomic sequence, “c.” for coding DNA sequence, “p.” for protein, “m.” for mitochondria, etc.).
Nomenclature
Over 16,500 pathogenicity assessments on 11,894 distinct variants in 338 genes causing neurological, endocrine, and nephrotic genetic disorders were performed on the sequencing data.
Materials and Methods, Data Collection and Storage
The BRCA1 and BRCA2 genes are tumor-suppressor genes. Mutations of these genes have been linked to hereditary breast and ovarian cancer.
Discussion, ‘How Does Evidence Fit With Biological Understanding?’
Lower penetrance was also an important consideration, especially in genes such as RAD51C, RAD51D, and BRIP1 that predispose to risk for ovarian cancer, given the uncertainties in how best to manage risk, difficulty of surveillance, and morbidity of intervention.
Considerations for Specific Phenotype Categories, Genes related to cancer phenotypes, Not recommended for addition to the SF v3.0 list
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
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.
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.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014661164205039096, 27/18416 alleles, homozygotes = 0).
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)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.