BRCA2 c.3111A>G, p.Gln1037=
NM_000059.4:c.3111A>G
Likely Benign
This synonymous BRCA2 variant lies outside key functional domains with no predicted splicing impact, extremely low population frequency, and supportive benign reports. Application of BP1_Strong and BP6_Supporting leads to a Likely Benign classification.
ACMG/AMP Criteria Applied
BP1
BP6
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.3111A>G
Protein Change
Q1037=
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.3111A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000401%
Extremely Rare
Highest in Population
African/African American
0.00618%
Rare
Global: 0.000401%
African/African American: 0.00618%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249562Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000401%, 1/249562 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00618%, 1/16178 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
6 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (1 clinical laboratories) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Likely benign
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.07
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows: a synonymous change (Q1037=), not predicted to introduce a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS1 is: "Strong 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))." The evidence for this variant shows: a synonymous substitution, not a missense change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PS2 is: "Confirmed de novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls (p ≤0.05, OR ≥4)." The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM1 is: "Moderate Apply PM1 for a variant located in a mutational hot spot or critical functional domain without benign variation." The evidence for this variant shows: a synonymous change at residue 1037, outside defined functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM2 is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The evidence for this variant shows: present at MAF=0.00000401 in gnomAD. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM3 is: "Supporting/Moderate/Strong Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrence of variants." The evidence for this variant shows: no Fanconi anemia phenotype or co-occurring variant data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: a synonymous substitution, no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PM5 is: "Strong Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows: a synonymous substitution, not a PTC. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PM6 is: "Unconfirmed de novo (no confirmation of maternity/paternity)." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PP1 is: "Supporting/Moderate/Strong Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: a synonymous variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PP3 is: "Supporting Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent variants." The evidence for this variant shows: SpliceAI predicts no impact (all scores <0.2). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for PP4 is: "Supporting/Moderate/Strong Use only in context of multifactorial likelihood clinical data for breast cancer phenotype." The evidence for this variant shows: no phenotype-specific multifactorial data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows: no reputable source reports this variant as pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BA1 is: "Stand Alone Filter allele frequency (FAF) >0.1% in gnomAD v2.1/v3.1." The evidence for this variant shows: FAF=0.00000401, well below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS1 is: "Strong Filter allele frequency (FAF) >0.01% in gnomAD v2.1/v3.1." The evidence for this variant shows: FAF=0.00000401, below 0.01%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS2 is: "Supporting/Moderate/Strong Applied in absence of recessive disease features (Fanconi Anemia)." The evidence for this variant shows: no unaffected adult heterozygote or Fanconi Anemia assessment. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS3 is: "Strong Well-established functional studies show no damaging effect on protein function." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BS4 is: "Strong Lack of segregation in affected family members (LR ≤0.05)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines the rule for BP1 is: "Strong Apply BP1_Strong for silent substitution outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." The evidence for this variant shows: Q1037= is outside defined domains (aa10-40, aa2481-3186) and SpliceAI predicts no impact (≤0.1). Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene or in cis with a pathogenic variant when phase is known." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: a single nucleotide change, not an indel in a repeat. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP4 is: "Supporting Missense or in-frame insertion/deletion variants inside a clinically important functional domain, or silent variants inside such domain IF no impact predicted." The evidence for this variant shows: a silent change outside functional domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP5 is: "Supporting Use only to capture combined LR against pathogenicity for co-observation with pathogenic variants in other breast–ovarian cancer genes." The evidence for this variant shows: no co-observation data. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines the rule for BP6 is: "Reputable source recently reports variant as benign, but evidence not available for independent evaluation." The evidence for this variant shows: reported as Likely benign by 6 labs and Benign by 1 lab in ClinVar and by ENIGMA. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines the rule for BP7 is: "Supporting Silent variant inside a clinically important functional domain IF BP4 met." The evidence for this variant shows: a silent variant outside domains and BP4 not met. Therefore, this criterion is not applied.