BRCA2 c.8456A>C, p.Asp2819Ala
NM_000059.4:c.8456A>C
Variant of Uncertain Significance (VUS)
This variant remains a VUS: moderate evidence for pathogenicity (PM1, PM5) and supporting evidence (PM2) are counterbalanced by supporting benign computational evidence (BP4) and lack of additional clinical or functional data.
ACMG/AMP Criteria Applied
PM1
PM2
PM5
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.8456A>C
Protein Change
D2819A
Location
Exon 19
(Exon 19 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2819 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.8456A>C
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
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 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 (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 2819 in gene BRCA2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.574
0.574
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_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.50primateai: T
Neutral: Show all
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 (+/–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 substitution (D2819A), not predicted to cause a null effect. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: predicted missense substitutions where a previously classified pathogenic variant results in the same amino acid change (no confirmed or predicted effect on mRNA splicing)." The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same D2819A change. 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 de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies have been reported. 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 (p≤0.05, OR≥4)." The evidence for this variant shows: no case–control or prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: it lies at amino acid 2819, within the BRCA2 DNA‐binding domain (aa 2481–3186), a critical functional domain. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent from controls in an outbred population, from gnomAD v2.1 and v3.1 (non‐cancer subsets)." The evidence for this variant shows: it is absent from gnomAD and other large population databases. 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 patients with a BRCA2‐related Fanconi Anemia phenotype and co‐occurrence of variants in trans in the same gene." The evidence for this variant shows: no Fanconi Anemia phenotype or trans‐variant data are reported. 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 due to in‐frame indels or stop-loss variants." The evidence for this variant shows: it is a missense substitution, not an indel. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
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: position D2819 has a different missense variant previously classified as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Co‐segregation with disease in multiple affected family members quantified by Bayes factor." The evidence for this variant shows: no segregation data are 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 a low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: BRCA2 disease mechanism is loss‐of‐function rather than missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: predicted impact via protein change (BayesDel no‐AF ≥0.30) or splicing (SpliceAI ≥0.2) inside a clinically important functional domain." The evidence for this variant shows: in silico predictions are mixed (REVEL 0.57, BayesDel unknown) and SpliceAI 0.01, below threshold. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Use only for multifactorial likelihood clinical data in a very specific phenotype context." The evidence for this variant shows: no such clinical data are available. 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 or likely pathogenic without available evidence." The evidence for this variant shows: ClinVar lists it as VUS. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Filter allele frequency (FAF) >0.1% in gnomAD non‐cancer subsets." The evidence for this variant shows: FAF = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: FAF >0.01% in gnomAD non‐cancer subsets." The evidence for this variant shows: FAF = 0%. 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(s) without Fanconi Anemia features." The evidence for this variant shows: no such observations are reported. 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 on protein function." The evidence for this variant shows: no functional studies are available. 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 members (LR ≤0.05)." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong: missense variants outside of clinically important functional domains with no splicing impact." The evidence for this variant shows: it is inside the DNA‐binding domain. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant gene, or in cis for a recessive gene." The evidence for this variant shows: no co‐occurrence data are available. 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 a repetitive region without a known function." The evidence for this variant shows: it is a missense change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: missense variants inside a clinically important functional domain with no predicted impact via protein change (BayesDel no‐AF ≤0.18) and no predicted impact on splicing (SpliceAI ≤0.1)." The evidence for this variant shows: SpliceAI 0.01 (no splicing impact) and computational predictors overall suggest no strong damaging effect. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Use only to capture combined LR against pathogenicity when variant co‐occurs with pathogenic variants in other genes." The evidence for this variant shows: no co‐occurrence data are reported. 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 without available evidence." The evidence for this variant shows: no such benign assertions exist. 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 variants with no splicing impact, or missense outside functional domains if BS3 met." The evidence for this variant shows: it is missense inside a functional domain. Therefore, this criterion is not applied.