NM_032043.3:c.736A>G (p.Ile246Val) in BRIP1 is a missense variant assessed under generic ACMG/AMP 2015 framework. No CSPEC/VCEP framework exists for BRIP1. This variant is present at very low frequency in gnomAD (v2.1 AF=0.01553%, grpmax FAF=0.09%; v4.1 AF=0.00700%, grpmax FAF=0.087%) with no homozygotes, meeting PM2 at supporting strength.1 Multiple in silico tools predict a benign effect: REVEL score 0.197, BayesDel score -0.206707, and SpliceAI predicts no splicing alteration (max delta 0.04), meeting BP4 at supporting strength.2 ClinVar reports this variant as Uncertain significance by 5 clinical laboratories and Likely benign by 4 clinical laboratories (VariationID 461180). No expert panel classification is available. The ClinVar review status is 1-star and does not meet thresholds for PP5 or BP6.3 No functional studies, segregation data, case-control data, or de novo observations were identified for this variant. Full-text review of three available publications (PMID:25741868, PMID:26467025, PMID:29641532) confirmed none mention NM_032043.3:c.736A>G.4 The only applicable criteria are PM2 (supporting pathogenic) and BP4 (supporting benign). With one supporting pathogenic and one supporting benign criterion, the variant defaults to Uncertain Significance (VUS) under the ACMG/AMP 2015 scoring framework.5
BRIP1
Final classification
VUS
BRIP1 c.736A>G · p.Ile246Val
BRIP1
NM_032043.3:c.736A>G (p.Ile246Val) in BRIP1 is a missense variant assessed under generic ACMG/AMP 2015 framework. No CSPEC/VCEP framework exists for BRIP1.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
BRIP1 c.736A>G
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
Gene diagram
· NM_032043.3 · variants mapped to exon structure
BRIP1
NM_032043.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases. gnomAD v2.1 overall AF=0.01553% (39/251,202 alleles, 0 homozygotes), grpmax FAF=0.09%. gnomAD v4.1 overall AF=0.00700% (113/1,613,894 alleles, 0 homozygotes), grpmax FAF=0.087%. All frequencies are below the 0.1% PM2 threshold for non-VCEP assessment.
gnomAD v2.1: AF=0.01553%grpmax FAF=0.09%0 homozygotes. gnomAD v4.1: AF=0.00700%
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.197 (below pathogenic threshold), BayesDel score is -0.206707 (benign-leaning), and SpliceAI predicts no splicing alteration (max delta 0.04). The concordance of multiple in silico tools predicting a benign effect meets BP4 at supporting strength.
REVEL=0.197 (benign)BayesDel=-0.206707 (benign)SpliceAI delta=0.04 (no effect). Concordant benign predictions from multiple in silico tools.
Assessed · not applied
Pathogenic
PS1
No prior pathogenic nucleotide change at the same amino acid position (p.Ile246) was identified in ClinVar or other curated sources.
PS2
No de novo confirmation data are available for this variant.
PS3
No functional studies were identified for NM_032043.3:c.736A>G (p.Ile246Val) or for a systematically characterized range that includes this residue.
PS4
No case-control prevalence data comparing affected individuals to controls are available for this variant.
PM1
Residue p.Ile246 does not lie within a statistically significant mutational hotspot (cancerhotspots.org) and no residue-specific functional domain characterization was identified in the case materials to support PM1 at domain level.
PM5
No pathogenic missense variant at the same codon (p.Ile246) with a different amino acid change was identified in ClinVar.
PM6
No de novo data are available.
PP1
No co-segregation data in multiple affected family members are available for this variant.
PP2
Insufficient constraint data are available to determine whether BRIP1 has a low rate of benign missense variation.
PP3
Multiple in silico tools predict no damaging effect.
PP4
No patient phenotype or family history data specific to this variant are available.
PP5
ClinVar classification for this variant is 'Uncertain significance' (5 clinical laboratories) and 'Likely benign' (4 clinical laboratories) with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
The highest observed population frequency is 0.12% in South Asian (gnomAD v2.1 SAS), which is well below the 1% BA1 threshold.
BS1
The highest observed population frequency is 0.12% in South Asian (gnomAD v2.1 SAS), which is below the 0.3% BS1 threshold for non-VCEP assessment.
BS2
No homozygous observations are recorded in gnomAD (0 homozygotes in both v2.1 and v4.1).
BS3
No functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant.
BS4
No segregation data showing lack of co-segregation with disease are available for this variant.
BP1
Although BRIP1 loss-of-function is a supported disease mechanism, BRIP1 is not a gene for which primarily truncating variants are known to cause disease.
BP2
No observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant disorder was identified.
BP5
No observation of this variant in a case with an alternate molecular basis for disease was identified.
BP6
ClinVar classification includes 4 clinical laboratories reporting 'Likely benign,' but the review status is 'criteria provided, single submitter' (1-star).
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 7.0017e-05; MAF= 0.00700%, 113/1613894 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00104299; MAF= 0.10430%, 95/91084 alleles, homozygotes = 0); grpmax FAF= 0.00087265.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000155254; MAF= 0.01553%, 39/251202 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00120868; MAF= 0.12087%, 37/30612 alleles, homozygotes = 0); grpmax FAF= 0.00090082.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.007%
· 113 / 1,613,894
0 hom · FAF 0.087%
0 hom · FAF 0.087%
South Asian 95 / 91,084 |
0.1% |
Middle Eastern 1 / 6,080 |
0.016% |
Admixed American 4 / 60,000 |
0.0067% |
Remaining individuals 1 / 62,488 |
0.0016% |
European (non-Finnish) 12 / 1,179,922 |
0.001% |
+ 5 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.016%
· 39 / 251,202
0 hom · FAF 0.09%
0 hom · FAF 0.09%
South Asian 37 / 30,612 |
0.12% |
Remaining individuals 1 / 6,126 |
0.016% |
European (non-Finnish) 1 / 113,514 |
0.00088% |
+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (4 clinical laboratories). (ClinVarID = 461180)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.197. BayesDel score = -0.206707.
Functional
Unknown Oncogenic Effect
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.
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.
Sources & reference links
Triaged references · 9 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
28796317 ↗
Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
24366376 ↗
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
29641532 ↗
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR