BRCA2 c.9111A>T, p.Gln3037His
NM_000059.4:c.9111A>T
Variant of Uncertain Significance (VUS)
Only BP4 (Supporting) is met based on computational evidence; all other criteria are not applied or unevaluable. The variant remains a Variant of Uncertain Significance (VUS) due to insufficient evidence for pathogenicity or benignity.
ACMG/AMP Criteria Applied
BP4
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.9111A>T
Protein Change
Q3037H
Location
Exon 23
(Exon 23 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 3037 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.9111A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000402%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000893%
Very Rare
Global: 0.000402%
European (non-Finnish): 0.000893%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 248824Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000402%, 1/248824 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000893%, 1/111986 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 3037 in gene BRCA2
Functional Summary
The BRCA2 Q3037H variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.395
0.395
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.57metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: “Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor +/–1,2), initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.” The evidence for this variant shows it is a missense change (Q3037H), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: “Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI ≤0.1)).” There is no previously established pathogenic variant with the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: “De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.” No information on de novo occurrence is available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: “Well-established in vitro or in vivo functional studies supportive of a damaging effect.” No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: “The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p ≤0.05 and OR ≥4).” No case–control or segregation data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: “Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation.” Although Q3037H lies within the DNA‐binding domain, there is no evidence that this position is a mutational hot spot or has established pathogenic variation. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines: “Supporting: Absent from controls in gnomAD v2.1 (non‐cancer) and v3.1 (non‐cancer).” The evidence shows the variant is present in gnomAD (MAF=0.000402%). Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: “Apply for patient with phenotype consistent with BRCA2‐related Fanconi Anemia and co‐occurring variants in the same gene.” No Fanconi anemia phenotype or trans observations are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: “Protein length changes due to in‐frame deletions/insertions in a non‐repeat region.” This is a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: “Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before.” This is not a PTC variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: “Assumed de novo, but without confirmation of paternity and maternity.” No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: “Co‐segregation with disease in multiple affected family members.” No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: “Missense variant in a gene with low rate of benign missense variation where missense is a common mechanism.” BRCA2 has numerous benign and pathogenic missense variants. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: “Supporting for missense variants inside a clinically important functional domain with BayesDel no‐AF ≥0.30 or predicted splicing (SpliceAI ≥0.2).” SpliceAI score is 0.05 (<0.2) but BayesDel no‐AF score is not available; computational predictions are mixed. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: “Use only with multifactorial likelihood clinical data for breast cancer phenotype.” No multifactorial or phenotype‐specific data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: “Reputable source reports variant as pathogenic.” ClinVar submissions are conflicting (VUS and Likely benign). Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: “Stand Alone: FAF >0.1% in gnomAD non‐cancer.” The variant frequency is 0.000402% (<0.1%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: “Strong: Filter allele frequency >0.01% in gnomAD non‐cancer.” The variant frequency is 0.000402% (<0.01%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: “Applied in absence of recessive disease features (Fanconi anemia phenotype) in healthy individuals.” No data on healthy adult observations are provided. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: “Well‐established functional studies show no damaging effect.” No functional assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: “Lack of segregation in affected family members.” No segregation analyses are reported. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines: “Silent or missense outside functional domain and no splicing predicted (SpliceAI ≤0.1).” The variant is inside the DNA‐binding domain. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: “Observed in trans with a pathogenic variant for a dominant disorder.” No such co‐occurrence data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: “In‐frame indel in a repetitive region.” This is a single nucleotide substitution. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines: “Supporting: Missense inside functional domain with no predicted impact via protein or splicing (BayesDel no‐AF ≤0.18 AND SpliceAI ≤0.1).” SpliceAI = 0.05; multiple in silico predictors (CADD, MetaSVM, MetaLR, PrimateAI) favor benign. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: “Use only with multifactorial likelihood clinical data for co‐observation with another gene variant.” No such data are provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: “Reputable source reports variant as benign.” ClinVar submissions are conflicting. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: “Silent or intronic variants outside conserved sites if BP4 met.” This is a missense variant. Therefore, this criterion is not applied.