BRCA2 c.7883T>G, p.Ile2628Arg
NM_000059.4:c.7883T>G
Variant of Uncertain Significance (VUS)
BRCA2 c.7883T>G (p.I2628R) remains VUS based on absence from population databases (PM2), novel missense change at a residue with other pathogenic variants (PM5), and multiple computational lines supporting deleterious effect (PP3), without sufficient additional evidence for pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PM5
PP3
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.7883T>G
Protein Change
I2628R
Location
Exon 17
(Exon 17 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 2628: I2628L, I2628V, I2628T, I2628M
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.7883T>G
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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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 2628: I2628L, I2628V, I2628T, I2628M
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.783
0.783
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
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.75primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 rule is: "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 a missense change (I2628R), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 rule 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)." The evidence for this variant shows no previously established pathogenic variant with the same amino acid change (I2628R). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 rule is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no evidence of a confirmed de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 rule is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." There are no functional studies available for BRCA2 I2628R. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 rule is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p-value ≤0.05 and OR ≥4)." No case-control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 rule is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." While I2628R lies within the BRCA2 DNA binding domain (aa2481-3186), there is insufficient evidence regarding absence of benign variation specific to this residue. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 rule is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows it is not present in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 rule is: "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurring variants in the same gene." There is no evidence of a Fanconi Anemia phenotype or a second BRCA2 variant in trans. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 rule is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." This is a missense change without alteration of protein length. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, PM5 rule is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence shows that a different pathogenic missense change at residue 2628 has been reported. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity." There is no de novo data for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 rule is: "Supporting 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, PP2 rule is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." BRCA2 has both pathogenic and benign missense variants; this rule is not met. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3 rule is: "Supporting Apply PP3 for missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.30 or for predicted splicing (SpliceAI ≥0.2)." The variant lies in the BRCA2 DNA binding domain (aa2481-3186) and has a REVEL score of 0.78 (>0.75). Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 rule is: "Use only for clinical multifactorial likelihood data with LR ≥2.08:1 for breast cancer phenotype." No multifactorial or phenotype data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 rule is: "Reputable source reports variant as pathogenic without available evidence." This variant is not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 rule is: "Stand Alone Filter allele frequency above 0.1% in gnomAD non-founder populations." The variant is absent (MAF=0%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 rule is: "Strong Filter allele frequency above 0.01% in gnomAD non-cancer populations." The variant is absent (MAF=0%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 rule is: "Applied in absence of Fanconi Anemia phenotype (≥4 healthy individuals)." No healthy adult data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 rule is: "Strong Well-established functional studies show no damaging effect." No functional studies demonstrate lack of damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 rule is: "Strong Lack of segregation in affected members (LR ≤0.05:1)." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1_Strong rule is: "Silent or in-frame variants outside clinically important domain with no predicted splicing impact." This is a missense variant inside a clinically important domain. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 rule is: "Observed in trans with a pathogenic variant for a dominant disorder." No evidence of trans configuration with a pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 rule is: "In-frame indel in a repetitive region without a known function." This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 rule is: "Supporting Missense or in-frame variants inside a clinically important domain with BayesDel no-AF ≤0.18 and SpliceAI ≤0.1." The variant has REVEL 0.78 supporting deleterious impact and SpliceAI minimal impact; it does not meet benign thresholds. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 rule is: "Use only for co-observation with pathogenic variants in other breast cancer genes with LR ≤0.48:1." No co-observation data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 rule is: "Reputable source reports variant as benign without evidence." This variant is not reported as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 rule is: "Supporting Silent or intronic variants outside conserved splice sites with no predicted splicing impact." This is a missense variant. Therefore, this criterion is not applied.