No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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.
Met at supporting strength: gnomAD v4.1 total allele frequency 5.5764e-05 is below the PM2 threshold of 0.0001, with zero homozygotes.
Met at supporting strength: BRIP1 disease-causing mutations are predominantly truncating, while rare missense variants comprise only a small proportion.
VUS: PM2 (supporting) plus BP1 (supporting) do not satisfy any generic ACMG/AMP pathogenic, likely pathogenic, benign, or likely benign combination.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 90 / 1,613,944 alleles. Recorded AF 5.5764e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.76865e-05; MAF= 0.00177%, 5/282702 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00705e-05; MAF= 0.00401%, 1/24956 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.607. Refer to the recorded PP3/BP4 rationale for interpretation.
12 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRIP1, a DEAH helicase, is altered by mutation and amplification in various cancers, including breast cancer and melanoma.
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 · 7 not met · 15 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No BRIP1-specific VCEP framework was identified; generic ACMG/AMP criteria were therefore applied.
The available evidence contains no proband-level de novo, parental-testing, segregation, meiosis, or informative non-segregation data for this variant.
No ClinGen CSPEC or BRIP1-specific VCEP framework was available, so generic ACMG/AMP rules were used.
The exact variant is NM_032043.3:c.1655T>C (p.Ile552Thr) in BRIP1.
The available evidence does not provide exact-variant case-control enrichment, a sufficiently specific phenotype, an alternative molecular explanation, or a qualifying ClinVar expert-panel classification.
No BRIP1-specific VCEP or gene-specific framework was available; the supplied generic population calibrations were applied.
The variant is rare in both gnomAD v2.1 and v4.1, supporting PM2 at Supporting strength, but its frequency is far below BA1 and BS1 thresholds.
Zero homozygotes alone does not establish BS2 because healthy-adult status, age, phenotype ascertainment, disease model, and penetrance are not available.
No criteria match.
No applicable BRIP1-specific VCEP or gene framework was identified, so the supplied generic ClinGen SVI PM2 Supporting threshold of <=0.0001 was used. The variant is present at 5.5764e-05 in gnomAD v4.1 and 1.768646843672843e-05 in gnomAD v2.1, both below 0.0001; all reported homozygote counts are zero. PM2 Supporting is met.
BP1 is met at supporting strength because the reviewed BRIP1 literature states that disease-causing mutations predominantly cause premature protein truncation or nonsense-mediated RNA decay, while only a small proportion are rare missense variants. The target is a missense substitution, NP_114432.2:p.Ile552Thr, so the gene's primarily truncating disease mechanism supports BP1.
Generic PP2 requires a gene with a low rate of benign missense variation and a substantial contribution of pathogenic missense variants. The available BRIP1 literature instead describes disease-causing variants as predominantly premature-truncating or nonsense-mediated-decay variants, with only a small proportion of rare missense variants disrupting critical functions. This does not establish the PP2 gene-level missense pattern.
The variant is a missense substitution, NM_032043.3:c.1655T>C (p.Ile552Thr), so PP3 must use the missense REVEL path only. The REVEL score is 0.607, below the generic ClinGen SVI supporting PP3 threshold of 0.644; therefore PP3 is not met. SpliceAI, BayesDel, and other computational predictors were not used for this criterion.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 142965 is an exact match, but the audit reports zero expert-panel submissions and only Uncertain significance laboratory submissions; therefore PP5 is not met. Ordinary laboratory assertions, aggregate labels, and cited papers cannot trigger PP5.
Apply PP5 only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; ordinary laboratory submissions and aggregate ClinVar labels are excluded.
No applicable BRIP1-specific VCEP or gene framework was identified, so the generic ACMG/AMP BA1 stand-alone threshold of >=0.05 was used. The highest reported all-comers allele frequency is 5.5764e-05 in gnomAD v4.1, and the highest reported population-specific frequency is 0.00012802 in the Remaining individuals population; both are far below 0.05. gnomAD v2.1 also reports a total allele frequency of 1.768646843672843e-05, with no homozygotes. Therefore, the available population data do not meet BA1.
No applicable BRIP1-specific VCEP or gene framework was identified, so the supplied generic SVI BS1 threshold of >=0.01 was used. The highest reported all-comers allele frequency is 5.5764e-05 in gnomAD v4.1; the highest listed subpopulation frequency is 0.00012802, and gnomAD v2.1 reports 1.768646843672843e-05 overall and 4.007052412245552e-05 in its highest listed subpopulation. These frequencies are below 0.01, so BS1 is not met.
The variant is a missense substitution, NM_032043.3:c.1655T>C (p.Ile552Thr), so BP4 must use the missense REVEL path only. The REVEL score is 0.607, above the generic ClinGen SVI supporting BP4 threshold of 0.29; therefore BP4 is not met. The SpliceAI score was not substituted because splice prediction does not assess missense protein tolerance.
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation 142965 is an exact match, but the audit reports zero expert-panel submissions and only Uncertain significance laboratory submissions; therefore BP6 is not met. Ordinary laboratory assertions, aggregate labels, and non-expert assertions cannot trigger BP6.
Apply BP6 only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; ordinary laboratory submissions and aggregate ClinVar labels are excluded.
PS1 requires an established pathogenic or likely pathogenic variant producing the same amino-acid change as NP_114432.2:p.Ile552Thr. The supplied evidence identifies the target variant as a ClinVar VUS but provides no independent same-amino-acid comparator with a reliable pathogenic classification and supporting evidence. The ClinVar classification itself was not used as evidence for PS1.
No applicable BRIP1-specific VCEP specification was identified, so generic ACMG/AMP criteria were used. The available case evidence does not document a confirmed de novo occurrence of NM_032043.3:c.1655T>C (NP_114432.2:p.Ile552Thr), parental genotypes, maternity/paternity confirmation, or an established phenotype consistent with a de novo BRIP1 disorder. Therefore PS2 cannot be assessed.
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity/paternity confirmed when applying strong evidence.
No variant-specific validated functional assay was identified for BRIP1 NM_032043.3:c.1655T>C (NP_114432.2:p.Ile552Thr). The exact-variant ClinVar record is classified as uncertain significance, and the available submission evidence explicitly states that functional studies have not been reported. OncoKB likewise reports no variant-specific reviewed functional evidence. Because there are no assay results, appropriate controls, biological readouts, or published calibration data to evaluate, PS3 cannot be applied.
Generic ACMG/AMP PS3: well-established functional studies supportive of a damaging effect may support pathogenicity; no qualifying assay evidence is available here.
Generic ACMG PS4 requires a statistically significant excess of the exact variant in affected individuals compared with appropriate controls. The available exact-variant ClinVar record reports submissions and broad cancer contexts but provides no analyzable case-control counts, odds ratio, confidence interval, or p-value for NM_032043.3:c.1655T>C; therefore PS4 cannot be assessed without inventing enrichment evidence.
PS4 requires statistically significant enrichment of the exact variant in affected cases versus appropriate controls; no numeric threshold is available because no qualifying enrichment statistic was reported.
No applicable BRIP1 VCEP or gene-specific framework was identified, and vcep_materials.json contains no BRIP1 domain-table entry. The supplied evidence therefore does not establish that residue 552 lies in a validated critical functional domain or hotspot suitable for PM1.
No applicable BRIP1-specific VCEP specification was identified, so generic ACMG/AMP PM3 was considered. BRIP1 is associated with recessive Fanconi anemia complementation group J in the biallelic disease context, but the available evidence for NM_032043.3:c.1655T>C (p.Ile552Thr) contains no documented affected proband with this variant and a pathogenic BRIP1 variant in trans, no confirmed homozygous or compound-heterozygous genotype, and no phase-resolved segregation or functional evidence establishing biallelic disease. ClinVar lists the exact variant as uncertain significance and the extracted case-report literature does not provide qualifying phase or affected-proband observations. PM3 therefore cannot be assessed from the available evidence.
Generic ACMG/AMP PM3: pathogenic or likely pathogenic variant observed in trans with the variant under assessment in an affected individual, with strength determined by the number and quality of independent observations; homozygous or compound-heterozygous affected genotypes may qualify when inheritance and variant pathogenicity are established.
PM5 requires a different missense substitution at the same residue with an established pathogenic or likely pathogenic classification. The supplied comparator collection contains no candidates, and the reviewed literature extracts do not provide a qualifying BRIP1 residue-552 comparator.
No applicable BRIP1-specific VCEP specification was identified, so generic ACMG/AMP criteria were used. The available case evidence does not document a suspected de novo occurrence of NM_032043.3:c.1655T>C (NP_114432.2:p.Ile552Thr) without parental testing, nor does it provide a proband phenotype or family-history context sufficient to support PM6. Therefore PM6 cannot be assessed.
Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the disease and no family history when parental testing is unavailable.
No applicable BRIP1-specific VCEP specification was identified, so generic ACMG/AMP criteria were used. The available case evidence does not report affected relatives carrying NM_032043.3:c.1655T>C, informative meioses, a segregation count, or a phenotype assessment in family members. Consequently, there is no usable segregation evidence for PP1.
Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members, with strength determined by the number and informativeness of meioses when sufficient data are available.
Generic ACMG PP4 requires a phenotype or family history highly specific for a disease with a single-gene etiology. The available record mentions broad ovarian, breast, uterine, and colorectal cancer contexts, but the exact-variant evidence does not provide a sufficiently specific phenotype, diagnostic features, or a disease-specific phenotype likelihood for this BRIP1 variant. A laboratory submission's PP4 signal is not independently sufficient and is not supported by an exact-variant paper extraction.
PP4 requires a phenotype or family history highly specific for a disease with a single-gene etiology; broad cancer diagnoses without disease-specific clinical features are insufficient.
BS2 requires observation of the variant in healthy adults, or in homozygous/compound-heterozygous state when the disorder is recessive, under the applicable disease model. The available gnomAD records report zero homozygotes but do not establish individual adult health status, age, penetrance, or phenotype, and no qualifying unaffected-adult observations are supplied. Therefore BS2 cannot be assessed from these data.
No variant-specific validated functional assay was identified for BRIP1 NM_032043.3:c.1655T>C (NP_114432.2:p.Ile552Thr). The exact-variant ClinVar record is classified as uncertain significance, and the available submission evidence explicitly states that functional studies have not been reported. OncoKB likewise reports no variant-specific reviewed functional evidence. Because there are no assay results, appropriate controls, biological readouts, or published calibration data demonstrating normal function, BS3 cannot be applied.
Generic ACMG/AMP BS3: well-established functional studies showing no damaging effect may support benignity; no qualifying assay evidence is available here.
No applicable BRIP1-specific VCEP specification was identified, so generic ACMG/AMP criteria were used. The available case evidence does not identify tested unaffected relatives who lack NM_032043.3:c.1655T>C, does not document their ages or phenotype ascertainment, and does not provide a valid non-segregation analysis. BS4 therefore cannot be assessed.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family, or non-segregation with disease in informative relatives, requires adequate phenotype and genotype ascertainment.
No applicable BRIP1-specific VCEP specification was identified, so generic ACMG/AMP BP2 was considered. The exact variant has been reported in ClinVar and cited clinical cohorts, but the available records and extracted paper findings do not document a phase-resolved observation showing NM_032043.3:c.1655T>C (p.Ile552Thr) in trans with a pathogenic or likely pathogenic BRIP1 variant, or in cis with a pathogenic BRIP1 variant. Cancer-cohort detection without explicit allelic phase, comparator pathogenicity, and a relevant inheritance interpretation is insufficient for BP2. The criterion therefore cannot be assessed rather than considered absent.
Generic ACMG/AMP BP2: the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for any disorder, when the phase and relevance of the comparator variant are established.
Generic ACMG BP5 requires the variant to be found in a patient with an alternative molecular basis for the phenotype, with the alternative explanation making this variant unlikely to be causal. The available evidence contains no documented alternative molecular diagnosis or qualifying coexisting pathogenic variant for the relevant patient; therefore BP5 cannot be assessed.
BP5 requires an alternative molecular basis for the patient's phenotype; no such patient-level evidence is available.
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
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 |
|---|
| Remaining individuals8 / 62,490 | 0.00013 |
| European (non-Finnish)82 / 1,180,032 | 6.9e-05 |
| African/African American1 / 24,956 | 4e-05 |
| European (non-Finnish)4 / 129,108 | 3.1e-05 |
This variant is present in gnomAD v4.1 (AF= 5.5764e-05; MAF= 0.00558%, 90/1613944 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00012802; MAF= 0.01280%, 8/62490 alleles, homozygotes = 0); grpmax FAF= 5.71e-05.
This variant is present in gnomAD v2.1 (AF= 1.76865e-05; MAF= 0.00177%, 5/282702 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00705e-05; MAF= 0.00401%, 1/24956 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_032043.3:c.1655T>C (p.Ile552Thr), so PP3 must use the missense REVEL path only. The REVEL score is 0.607, below the generic ClinGen SVI supporting PP3 threshold of 0.644; therefore PP3 is not met. SpliceAI, BayesDel, and other computational predictors were not used for this criterion.
The variant is a missense substitution, NM_032043.3:c.1655T>C (p.Ile552Thr), so BP4 must use the missense REVEL path only. The REVEL score is 0.607, above the generic ClinGen SVI supporting BP4 threshold of 0.29; therefore BP4 is not met. The SpliceAI score was not substituted because splice prediction does not assess missense protein tolerance.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.607. BayesDel score = 0.0109582.
9 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
In CHEK2, ATM, BRIP1 and PALB2, most of the disease-causing mutations result in premature protein truncation or nonsense-mediated RNA decay through nonsense codons or translational frameshifts. A small proportion is likely to be rare missense variants that disrupt critical functions.
Location Page 18, section ‘Rare moderate-penetrance breast cancer susceptibility genes’
Context Gene-level review of breast-cancer susceptibility alleles; no variant-specific assay or cohort for BRIP1 p.Ile552Thr.
We also observed 32 truncations in BRCA1 and BRCA2 interacting proteins: PALB2 (n=12, 4 in stomach, 3 in ovarian, 2 in head and neck and each in breast, lung and prostate cancers), BRIP1 (n=16, 3 each in breast, ovarian and lung, 2 in stomach, 1 each in GBM, HNSC, KIRC, LGG and UCEC), and BAP1 (n=2, in kidney) and BARD1 (n=2, 1 each in PRAD and BRCA).
Results, ‘Genes significantly associated with cancer predisposition’; Results, ‘LOH analysis of rare truncation and missense variants’
BRIP122,27 Ovarian, possibly breast Ovarian cancer, 5.8%
Table 1; Figure 1; Table 3
Genes analyzed with the multigene panel were categorized as high- or moderate-penetrance based on expected lifetime risks of cancer (≥40% versus <40% or unknown) associated with the respective cancer predisposition syndrome (Table 1).21-26 The genes underlying LS, adenomatous polyposis (APC and MUTYH) and hamartomatous polyposis (BMPR1A, PTEN, SMAD4, and STK11) syndromes, BRCA1/2, familial atypical multiple mole melanoma syndrome (CDKN2A and CDK4), hereditary diffuse gastric cancer (CDH1), and Li-Fraumeni syndrome (TP53) were categorized as high-penetrance, whereas the remaining eight genes (ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C, and RAD51D) were considered moderate-penetrance.
Methods, Germline Sequencing/Interpretation; Results, Germline Findings
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= 5.5764e-05; MAF= 0.00558%, 90/1613944 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00012802; MAF= 0.01280%, 8/62490 alleles, homozygotes = 0); grpmax FAF= 5.71e-05.
This variant is present in gnomAD v2.1 (AF= 1.76865e-05; MAF= 0.00177%, 5/282702 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00705e-05; MAF= 0.00401%, 1/24956 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories). (ClinVarID = 142965)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.607. BayesDel score = 0.0109582.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRIP1, a DEAH helicase, is altered by mutation and amplification in various cancers, including breast cancer and melanoma.
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.