BRCA2 c.6833T>G, p.Ile2278Ser
NM_000059.4:c.6833T>G
Variant of Uncertain Significance (VUS)
The variant remains a VUS: PM2 (Supporting) and PM5 (Moderate) provide some pathogenic evidence but are counterbalanced by BP1 (Strong) benign evidence, with no additional data to resolve the conflict.
ACMG/AMP Criteria Applied
PM2
PM5
BP1
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.6833T>G
Protein Change
I2278S
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 2278: I2278L, I2278V, I2278T
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.6833T>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (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
ClinVar reports other pathogenic variants at position 2278: I2278L, I2278V, I2278T
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.313
0.313
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: 0.29polyphen_prediction: benignmetasvm: 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, 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 it is a missense change (I2278S), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no previously established pathogenic I2278S variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No de novo data are available for this variant. 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." No functional assay data exist for I2278S. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: prevalence of variant in affected individuals is significantly increased compared to controls (p ≤0.05, OR ≥4)." No case-control data exist. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate: variant located in a mutational hot spot or well-studied functional domain without benign variation." I2278S lies outside the defined PALB2 binding domain (aa10-40) and DNA-binding domain (aa2481-3186). Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: absent from controls in gnomAD v2.1 (non-cancer) and v3.1 (non-cancer), read depth ≥25." The evidence for this variant shows it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting/Moderate/Strong: observed in trans with a pathogenic variant in patients with BRCA2-related Fanconi Anemia." No FA or trans compound heterozygosity data exist. 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 indel or stop-loss that is not predicted to impact splicing." This is a missense change, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: "Moderate: novel missense change at an amino acid where a different missense change determined to be pathogenic has been seen." The evidence for this variant shows that another pathogenic missense at residue I2278 has been reported. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Supporting: assumed de novo, without confirmation of paternity/maternity." No such data exist. 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." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." BRCA2 does not have a low rate of benign missense variation, and many missense variants are VUS. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: computational evidence of impact (BayesDel no-AF ≥0.30 or SpliceAI ≥0.2)." In silico tools (CADD, PolyPhen, REVEL 0.31) and SpliceAI (0.01) predict no impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting/Moderate/Strong: phenotype specificity in BRCA2 disorders using multifactorial likelihood data." No phenotype or multifactorial data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: reputable source reports variant as pathogenic without available evidence." This is discouraged and no such reports exist. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: allele frequency >0.1% in gnomAD non-cancer populations." The variant is absent from gnomAD. 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 >0.01% in gnomAD non-cancer populations." The variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Supporting/Moderate/Strong: observed in healthy adults without Fanconi Anemia features." No such data exist. 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." No functional data exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong/Moderate/Supporting: lack of segregation in affected family members." No segregation data exist. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong: missense variant outside clinically important functional domains (aa10-40 or aa2481-3186) and no splicing impact (SpliceAI ≤0.1)." I2278S lies outside those domains and SpliceAI=0.01. Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: observed in trans with a pathogenic variant for a fully penetrant dominant disorder." No such data exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: in-frame indels in repetitive regions without known function." This is a missense variant, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: missense inside a functional domain with no impact predicted (BayesDel ≤0.18 and SpliceAI ≤0.1)." The variant is outside defined domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting/Moderate/Strong: co-observation with pathogenic variants in other genes without specific phenotype." No such data exist. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: reputable source reports variant as benign without available evidence." No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: silent or intronic variants outside splice sites with no splicing impact after BP4 met." This variant is missense. Therefore, this criterion is not applied.