BRCA2 c.4567G>A, p.Gly1523Ser
NM_000059.4:c.4567G>A
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Uncertain Significance (VUS)
2 publications
REVEL Score
0.503
Uncertain (High)
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.4567G>A
Protein Change
G1523S
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 1523: G1523R, G1523D, G1523V
Variant interpretation based on transcript NM_000059.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
2 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories).
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 1523: G1523R, G1523D, G1523V
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The BRCA2 G1523S variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.503
0.503
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.16
polyphen_prediction: benign
metasvm: T
metalr: T
primateai: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
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 (+/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows it is a missense change (G1523S) and therefore does not meet the null variant criteria. 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 is observed. The evidence for this variant does not show an identical protein change by a different nucleotide change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS2 is used for de novo occurrences with confirmed maternity and paternity in a patient with the disease. There is no de novo evidence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing and standard ACMG guidelines, PS3 is applied when well‐established in vitro or in vivo functional studies show a damaging effect. The functional studies for the BRCA2 G1523S variant have not been performed and have not demonstrated a damaging effect. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PS4 requires that the prevalence of the variant in affected individuals is significantly increased compared to controls. There is no case‐control data provided for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM1 applies for variants located in a mutational hotspot or a well‐established functional domain without benign variation. The evidence does not indicate that this residue is in such a critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to standard ACMG guidelines and VCEP modifications for PM2, the rule is: 'Absent from controls in an outbred population' (e.g., not found in gnomAD v2.1 or v3.1). The evidence for this variant shows a minor allele frequency of 0%, and it is not present in gnomAD. Therefore, this criterion is applied at a Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to VCEP guidelines for PM3, this criterion is used for recessive disorders with evidence of in trans occurrence with another pathogenic variant. The evidence for this BRCA2 variant does not include such data. 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 in non-repetitive regions, which is not applicable for a missense variant. The evidence shows a missense change and not a protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, PM5 is defined as: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence indicates that although this is a novel missense change (G1523S), a different missense change at the same amino acid has been reported as pathogenic. Therefore, this criterion is applied at a Moderate strength.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM6 is used for assumed de novo variants without confirmation. There is no evidence to suggest de novo occurrence for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP1 requires co-segregation with disease in multiple affected family members. There is no segregation data provided for this variant. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP2 applies in genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. Although BRCA2 can be sensitive to missense changes, the evidence does not provide sufficient information to apply PP2 for this variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP3 is used when multiple computational tools predict a deleterious effect on the gene or protein. In this case, the computational predictions are predominantly benign and instead support application of BP4. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP4 is applied when the patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. The evidence for this variant does not include specific phenotype or multifactorial likelihood data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP5 is used when a reputable source reports the variant as pathogenic, but the details are not available for independent evaluation. The current evidence in ClinVar reports the variant as VUS, and no definitive pathogenic external assertion is provided. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP and standard ACMG guidelines, BA1 is applied as a stand-alone rule for variants with an allele frequency greater than 5% in control populations. The evidence shows a frequency of 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS1 is applied when the allele frequency is greater than expected for the disorder. The evidence shows that the variant is absent in population databases (0% frequency). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS2 is used when the variant is observed in a healthy adult with no signs of a dominant disorder. There is no evidence provided regarding healthy individuals carrying this variant. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS3 is applied when well-established functional studies show no damaging effect on protein function. In this case, appropriate functional studies are lacking. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS4 is used when there is a lack of segregation in affected family members. There is no segregation data provided for this variant. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP1 is applied for missense variants in genes where only truncating variants cause disease. In BRCA2, both truncating and missense variants can be pathogenic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 is used when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disease. There is no evidence of such findings. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP3 is applied to in-frame deletions in repetitive regions without a known functional impact. This variant is a missense change rather than an in-frame deletion, so this criterion is not applicable.
BP4
BP4 (Supporting)
According to standard ACMG guidelines and the VCEP modifications for BP4, the rule is: 'Missense variants with multiple lines of computational evidence suggesting no impact on gene or gene product' (e.g., low CADD score, benign predictions by PolyPhen-2, MetaSVM, MetaLR, and PrimateAI, and no predicted splicing impact by SpliceAI). The evidence for this variant shows a low CADD score (1.16) and multiple in silico tools supporting a benign effect. Therefore, this criterion is applied at a Supporting strength.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP5 is applied when a variant is observed in a case with another pathogenic variant that could explain the phenotype. There is no evidence suggesting such co-occurrence for this variant. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source provides a benign classification without available evidence for independent evaluation. The available ClinVar submissions list this variant as VUS, so BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines and VCEP modifications, BP7 is applied to silent or intronic variants with no predicted impact on splicing, or missense variants outside clinically important domains meeting splicing prediction thresholds. The variant in question is a missense change within the protein and does not meet the criteria for BP7. Therefore, this criterion is not applied.