BRCA2 c.9958C>G, p.Pro3320Ala
NM_000059.4:c.9958C>G
Variant of Uncertain Significance (VUS)
This missense variant p.P3320A in BRCA2 is absent from population databases (PM2_Supporting) and is a predicted benign missense outside key functional domains with no splicing impact (BP1_Strong). No additional evidence from functional studies, segregation, phenotypic specificity, or case-control data is available. Therefore, the variant remains classified as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.9958C>G
Protein Change
P3320A
Location
Exon 27
(Exon 27 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 3320 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.9958C>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
No evidence of other pathogenic variants at position 3320 in gene BRCA2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.125
0.125
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: 2.29
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) 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, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (p.P3320A), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change with same amino acid change.' The evidence for this variant shows: there is no previously established pathogenic variant causing p.P3320A. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no information on de novo occurrence or parental testing. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect.' The evidence for this variant shows: no functional characterization has been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls.' The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate: Variant located in a mutational hot spot and/or well-studied functional domain without benign variation.' The evidence for this variant shows: p.P3320A is outside defined BRCA2 functional domains (PALB2 binding aa 10–40; DNA-binding aa 2481–3186). Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Absent from controls in gnomAD v2.1 and v3.1.' The evidence for this variant shows: not found in population databases (gnomAD MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Apply for patient with phenotype consistent with BRCA2-related Fanconi Anemia and co-occurring variants in the same gene.' The evidence for this variant shows: no information on FANCONI anemia phenotype or co-occurring variants. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in-frame deletions/insertions in a non-repetitive region.' The evidence for this variant shows: it is a single amino acid substitution, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence for this variant shows: no other pathogenic variant reported at codon 3320. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism.' The evidence for this variant shows: BRCA2 has both benign and pathogenic missense variants; no specific data supports PP2. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting: Missense variant inside a functional domain with predicted impact via protein change (BayesDel ≥0.30).’ The evidence for this variant shows: it is outside defined domains and REVEL=0.12, CADD=2.29, SpliceAI=0. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Supporting: Phenotype specificity based on multifactorial likelihood data.' The evidence for this variant shows: no patient phenotype or multifactorial data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' The evidence for this variant shows: not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: Allele frequency >0.1% in gnomAD.' The evidence for this variant shows: MAF=0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: Filter allele frequency >0.01% in gnomAD.' The evidence for this variant shows: MAF=0% in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in healthy adult individuals in absence of Fanconi Anemia features.' The evidence for this variant shows: no healthy adult data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong: Well-established functional studies show no damaging effect.' The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Strong: Silent or missense variant outside functional domain and no splicing predicted (SpliceAI ≤0.1).' The evidence for this variant shows: p.P3320A is outside defined domains and SpliceAI=0. Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observation of the variant in trans with a pathogenic variant for a dominant disorder.' The evidence for this variant shows: no such co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive region without known function.' The evidence for this variant shows: it is a single amino acid substitution, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting: Missense variant inside functional domain with no predicted impact.' The evidence for this variant shows: it is outside defined domains, despite benign computational scores. Therefore, this criterion is not applied under gene-specific BP4.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting: Observation in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no co-observation with other pathogenic variants. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign.' The evidence for this variant shows: not found in any such source. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting: Silent or intronic variant outside splice motifs with no predicted impact, IF BP4 met.' The evidence for this variant shows: it is a missense substitution, not eligible for BP7. Therefore, this criterion is not applied.