BRCA2 c.7765C>A, p.Pro2589Thr
NM_000059.4:c.7765C>A
Variant of Uncertain Significance (VUS)
Only PM1 (Moderate), PM2 (Supporting) and BP4 (Supporting) criteria are met. This combination is insufficient for classification beyond Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM1
PM2
BP4
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.7765C>A
Protein Change
P2589T
Location
Exon 16
(Exon 16 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2589 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
Loading genome browser...
HGVS InputNM_000059:c.7765C>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.000398%
South Asian: 0.00327%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251418Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251418 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00327%, 1/30616 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 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 2589 in gene BRCA2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.82primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for PVS1: "Very Strong Null variant (nonsense, frameshift, splice site ... loss of function) in a gene where LOF is a known mechanism of disease." The evidence shows this is a missense variant (P2589T), not a null variant. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: "Strong Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant has the same amino acid change." There is no previously established pathogenic variant with P2589T. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PS2: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no evidence of de novo occurrence. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines for PS3: "Well-established in vitro or in vivo functional studies supportive of a damaging effect." No functional studies exist for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4: "Prevalence in affected individuals is significantly increased compared to controls (OR ≥4, p ≤0.05)." No case-control data are available. Therefore, PS4 is not applied.
PM1
PM1 (Moderate)
According to standard ACMG guidelines for PM1: "Located in a mutational hot spot and/or critical functional domain without benign variation (Moderate)." The variant P2589T lies within the BRCA2 DNA binding domain (aa2481–3186), a critical functional region. Therefore, PM1 is applied at Moderate strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2: "Supporting Absent from controls in gnomAD v2.1 (non-cancer exome) and gnomAD v3.1 (non-cancer)." The variant is extremely rare (MAF = 0.000398%, 1/251418 alleles) and absent in non-cancer subset. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines for PM3: "Apply for BRCA2-related Fanconi Anemia phenotype with co-occurrence of variants." No Fanconi Anemia phenotype or co-occurrence data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM4: "Protein length changes due to in-frame indels or stop-loss variants." This is a missense variant. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM5: "A different amino acid change at the same codon is pathogenic (Moderate)." No other pathogenic change at codon 2589 is reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM6: "Assumed de novo without confirmation of paternity and maternity." No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1: "Co-segregation with disease in multiple affected family members (Supporting to Strong)." No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP2: "Missense variant in a gene with a low rate of benign missense variation and pathogenic missense is common." BRCA2 has both benign and pathogenic missense variants; no clear evidence supports PP2. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PP3: "Supporting predicted impact via protein change (BayesDel ≥0.30) or splicing (SpliceAI ≥0.2)." In silico predictions are mixed and SpliceAI = 0.04. Thus, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for PP4: "Phenotype-based multifactorial likelihood data required for breast cancer." No such data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP5: "Reputable source classifies variant as pathogenic." ClinVar reports this variant as VUS. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: "Filter allele frequency >0.001 in gnomAD non-cancer indicates stand-alone benign." The variant frequency (0.00000398) is below this threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: "Filter allele frequency >0.0001 (Strong) or >0.00002 (Supporting) and ≤0.0001." The variant frequency (0.00000398) is below both thresholds. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2: "Observed in healthy adults without recessive disease phenotype (Fanconi Anemia)." No phenotype data on carriers are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3: "Well-established functional studies show no damaging effect." No such studies exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for BS4: "Lack of segregation in affected family members." No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines for BP1: "Missense variant outside clinically important domain and no splicing impact." This variant lies inside the DNA binding domain. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP2: "Observed in trans with a pathogenic variant for a dominant disorder." No co-occurrence data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP3: "In-frame indels in repetitive regions without known function." This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines for BP4: "Supporting No predicted impact via protein change or splicing (BayesDel ≤0.18 and SpliceAI ≤0.1)." Computational evidence is mixed with SpliceAI = 0.04 and overall in silico favoring benign. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines for BP5: "Cases with pathogenic variants in other breast-ovarian cancer genes without specific phenotype." No such co-observations are reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP6: "Reputable source classifies variant as benign." ClinVar reports this variant as VUS. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for BP7: "Silent or intronic variants outside splice sites with no impact." This variant is missense. Therefore, BP7 is not applied.