BRCA2 c.5111G>T, p.Arg1704Ile
NM_000059.4:c.5111G>T
Variant of Uncertain Significance (VUS)
R1704I in BRCA2 remains a VUS. Applied criteria include PM5 (Moderate) and PM2 (Supporting) supporting pathogenicity, and BP1 (Strong) supporting benign impact. Conflicting evidence is insufficient to reach a definitive classification.
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.5111G>T
Protein Change
R1704I
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 1704: R1704G
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.5111G>T
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
2 publications
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This missense variant replaces arginine with isoleucine at codon 1704 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain Significance (1 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 1704: R1704G
PM5 criterion applied.
Functional Summary
The BRCA2 R1704I 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
0.141
0.141
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: 0.54polyphen_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, PVS1 applies to null variants in a gene where LOF is a known mechanism. The variant is a missense change (R1704I), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when the amino acid change is identical to a previously established pathogenic variant. There is no previous report of R1704I as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for confirmed de novo occurrence. No parental testing or de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies showing a damaging effect. No functional studies have been performed for R1704I. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 applies when case-control data show significant enrichment in affected individuals. No case-control or prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants located within critical functional domains (PALB2 binding aa10-40 or DNA-binding aa2481-3186). R1704I lies outside these regions. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 supporting: "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer) and v3.1." The variant is absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies when co-occurring variants are observed in patients with a Fanconi Anemia phenotype. No such phenotype or co-occurrence data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop losses. R1704I is a missense change without length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, PM5 moderate: "Novel missense change at an amino acid residue where a different missense change has been determined to be pathogenic." Other missense variants at residue 1704 have been reported as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies for presumed de novo occurrences without confirmation. No de novo or parental data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation data in affected family members. No segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies for missense variants in genes where such variants rarely cause disease. BRCA2 has known pathogenic missense variants. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to missense variants inside critical domains with computational evidence of impact. R1704I lies outside defined domains and computational tools predict no impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires specific phenotype data to calculate a likelihood ratio. No detailed clinical phenotype is provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when multiple reputable sources report a variant as pathogenic. ClinVar reports R1704I as VUS only. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies for allele frequency >0.1% in gnomAD. R1704I is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies for allele frequency >0.01%. R1704I is absent from databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies for observations in healthy adults without recessive phenotype. No such observational data are provided. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well-established functional studies showing no damaging effect. No functional studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, BP1_Strong: "Missense variants outside critical domains and no predicted impact on splicing." R1704I lies outside defined domains and SpliceAI ≤0.1. Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when a variant is observed in trans with a pathogenic variant for a dominant disorder. No trans-observation data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, BP3 applies to in-frame indels in repetitive regions. R1704I is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies only to variants inside critical domains with no impact predicted. R1704I lies outside domains; despite benign computational evidence, BP4 is not applied per VCEP. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 requires co-observation with another pathogenic variant in a case. No such co-observation data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when multiple reputable sources report a variant as benign. No such reports exist for R1704I. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants outside splice sites. R1704I is a missense variant. Therefore, this criterion is not applied.