BRCA2 c.426-22G>T, p.?
NM_000059.4:c.426-22G>T
Likely Benign
This BRCA2 intronic variant c.426-22G>T is supported by four benign criteria (BS1_Supporting, BP4, BP6, BP7_Supporting) with no pathogenic evidence, resulting in a final classification of Likely Benign.
ACMG/AMP Criteria Applied
BS1
BP4
BP6
BP7
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.426-22G>T
Protein Change
?
Location
Exon 4
(Exon 4 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.426-22G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00249%
Rare
Highest in Population
Remaining individuals
0.014%
Low Frequency
Global: 0.00249%
Remaining individuals: 0.014%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 280754Alt: 7Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00249%, 7/280754 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.014%, 1/7162 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.43
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 at canonical ±1,2 splice positions in BRCA2. The evidence for this variant shows it is at position c.426-22, outside the ±1,2 splice site. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant has the same amino acid change as a known pathogenic variant. This is an intronic variant with no predicted protein change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies to confirmed de novo occurrences. No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP and standard ACMG guidelines, PS3 requires well‐established functional studies showing a damaging effect. No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires a statistically significant increase in variant prevalence in affected individuals. No case-control or cohort data exist for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants within critical functional domains. This variant is intronic outside of protein domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2_Supporting requires absence from controls in gnomAD. The evidence for this variant shows a MAF of 0.00249% in gnomAD. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to variants in trans with a pathogenic variant in confirmed Fanconi Anemia cases. No FA data are available for this variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes such as in-frame indels. This variant is intronic. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies to novel missense changes at residues with known pathogenic missense mutations. This variant is intronic. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo without confirmation. No de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation with disease in multiple 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 to missense variants in genes with low rates of benign missense variation. This variant is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 requires computational evidence supporting a deleterious effect. In silico splicing predictors (SpliceAI 0.01) and CADD (-0.43) predict no impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies when patient phenotype matches gene-specific disease with high specificity. No phenotypic data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to assertions of pathogenicity by reputable sources. The variant is reported as likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires a filter allele frequency >0.1% in gnomAD. The variant MAF is 0.00249%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Supporting) Strength Modified
According to VCEP guidelines, BS1_Supporting is: "Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001)". The evidence for this variant shows a MAF of 0.00249% in gnomAD. Therefore, this criterion is applied at Supporting strength because the allele frequency falls within the specified range.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies in the absence of a Fanconi Anemia phenotype in multiple individuals. No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well‐established functional studies showing no damaging effect. No functional studies have been performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires 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 to silent or missense variants outside functional domains with no splice impact. This is an intronic variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observations in trans with a pathogenic variant in autosomal dominant disorders. No such observations exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame deletions/insertions in repetitive regions. This variant is intronic with no indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 is: "Intronic variants outside of the native donor and acceptor splice sites (i.e. not ±1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1)". The evidence for this variant shows it is at position –22 from the exon and SpliceAI predicts no impact (0.01). Therefore, this criterion is applied at Supporting strength because it meets the specified splicing criteria.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies when a variant is observed in a case with an alternate molecular basis for disease. No such co-occurrence data are available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows ClinVar assertions of Likely Benign by two clinical laboratories without full data. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
According to VCEP guidelines, BP7_Supporting is: "Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met". The evidence for this variant shows it is at position –22 and BP4 is met. Therefore, this criterion is applied at Supporting strength because it lies beyond the conserved splice motif and computational evidence supports no impact.