BRCA2 c.8254A>T, p.Ile2752Phe
NM_000059.4:c.8254A>T
COSMIC ID: COSM5575339
Variant of Uncertain Significance (VUS)
Variant NM_000059.4:c.8254A>T (I2752F) in BRCA2 remains a VUS. It is absent from population databases (PM2_Supporting) but lacks other supportive or strong evidence. Insufficient data to classify as benign or pathogenic.
ACMG/AMP Criteria Applied
PM2
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.8254A>T
Protein Change
I2752F
Location
Exon 18
(Exon 18 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2752 in gene BRCA2
Alternate Identifiers
COSM5575339
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.8254A>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
4 publications
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2752 of the BRCA2 protein (p.Ile2752Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21232165, 22366370). ClinVar contains an entry for this variant (Variation ID: 52538). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
This missense variant replaces isoleucine with phenylalanine at codon 2752 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000302) and in suspected hereditary breast and ovarian cancer families (PMID: 21232165, 22366370). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3348, respectively (PMID: 31131967). 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.
The BRCA2 c.8254A>T (p.Ile2752Phe) variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 38785549 (2024), 22366370 (2012), 21232165 (2011)). This variant was reported as being likely benign in a multifactorial likelihood study (PMID: 31131967 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
This missense variant replaces isoleucine with phenylalanine at codon 2752 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000302) and in suspected hereditary breast and ovarian cancer families (PMID: 21232165, 22366370). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3348, respectively (PMID: 31131967). 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 Likely benign (2 clinical laboratories) and 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
No evidence of other pathogenic variants at position 2752 in gene BRCA2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.511
0.511
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
Pathogenic:
polyphen_prediction: probably_damagingmetalr: D
Benign:
CADD: 2.47metasvm: 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 (nonsense, frameshift, splice site, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' This variant is a missense change (I2752F). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PS1 applies when the same amino acid change as a previously established pathogenic variant occurs, regardless of nucleotide change.' There is no report of another variant causing I2752F classified as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PS2 applies for de novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' No de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PS3 applies when well-established in vitro or in vivo functional studies show a damaging effect on the gene or gene product.' No functional studies have been performed on this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'PS4 Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls.' No case-control or case prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PM1 applies to variants located in mutational hot spots or critical functional domains without benign variation.' Although I2752F is within the BRCA2 DNA-binding domain (aa 2481–3186), there is no evidence of a mutational hot spot at this residue or absence of benign variation in this region. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'PM2 Supporting: Absent from controls in gnomAD v2.1 and v3.1 (non-cancer) with adequate read depth.' This variant is not observed in gnomAD and meets read depth requirements. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: 'PM3 applies for BRCA1/2-related Fanconi Anemia phenotype with co-occurring variants in the same gene.' There is no Fanconi Anemia phenotype or evidence of a second variant in BRCA2. 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 deletions/insertions or stop-loss variants.' I2752F is a missense variant without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PM5 applies to novel missense changes at a residue where a different pathogenic missense change has been seen.' No other pathogenic missense at residue I2752 is reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PM6 applies to presumed de novo variants without confirmation of parentage.' No de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP1 applies for 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 applies for missense variants in a gene with a low rate of benign missense variation and where missense is a common mechanism.' BRCA2 has numerous benign and uncertain missense variants; therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP3 Supporting: BayesDel no-AF score ≥0.30 AND SpliceAI ≥0.2 for predicted splicing OR BayesDel no-AF score ≥0.30 for predicted protein impact inside a functional domain.' SpliceAI ≤0.1 and BayesDel no-AF score is not available. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: 'PP4 applies when patient phenotype is highly specific for a gene.' No specific phenotype data linking I2752F to BRCA2-related cancer are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'PP5 applies to assertions from reputable sources without available evidence.' ClinVar submissions include conflicting classifications and PP5 is deprecated. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BA1 Stand Alone: Filter allele frequency >0.001 in gnomAD.' The variant allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS1 Strong: Filter allele frequency >0.0001 in gnomAD.' The variant allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS2 applies for variants observed in healthy adults without recessive disease phenotype.' No such observations are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'BS3 Strong: Well-established functional studies show 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 applies for lack of segregation in affected family members.' No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP1 applies for missense or in-frame variants outside a clinically important functional domain with no splicing impact.' I2752F is inside the DNA-binding domain. Therefore, this criterion is not applied.
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 or in cis for a recessive disorder.' No such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'BP3 applies to in-frame indels in repetitive regions without functional impact.' This variant is missense, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP4 Supporting: BayesDel no-AF score ≤0.18 AND SpliceAI ≤0.1 for variants inside a functional domain.' SpliceAI is ≤0.1 but BayesDel no-AF score is not available. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP5 applies when variant is found in a case with an alternate molecular basis for disease.' No data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'BP6 applies to assertions of benign from reputable sources without evidence.' This criterion is deprecated. Therefore, not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: 'BP7 applies to silent or intronic variants with no splicing impact.' This is a missense variant. Therefore, this criterion is not applied.