BRCA2 c.-39-14C>T, p.?
NM_000059.4:c.-39-14C>T
Variant of Uncertain Significance (VUS)
The variant c.-39-14C>T in BRCA2 remains classified as VUS due to only two supporting criteria (PM2, BP6) and absence of stronger pathogenic or benign evidence.
ACMG/AMP Criteria Applied
PM2
BP6
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.-39-14C>T
Protein Change
?
Location
Exon 1
(Exon 1 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.-39-14C>T
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
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
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
Functional Summary
The BRCA2 -39-14c>T variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.91
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 (donor/acceptor +/−1,2), 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 intronic at c.-39-14, outside of canonical splice sites and not predicted to cause loss of function. Therefore, this criterion is not applied because the variant does not meet null variant criteria.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Apply PS1 for exonic and intronic variants with same predicted impact on splicing as a previously classified pathogenic variant or for missense substitutions resulting in the same amino acid change as an established pathogenic variant." The evidence for this variant shows: no amino acid change and no match to a previously classified pathogenic variant. Therefore, this criterion is not applied because there is no established pathogenic variant with the same effect.
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 has been documented. Therefore, this criterion is not applied because de novo status is not confirmed.
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 conducted. Therefore, this criterion is not applied because functional evidence is lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Case-control studies show statistically significant increased prevalence in affected individuals (p ≤ 0.05 and OR ≥ 4.0)." The evidence for this variant shows: no case-control data available. Therefore, this criterion is not applied due to absence of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
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 is intronic, outside known functional domains. Therefore, this criterion is not applied because it does not affect a critical domain.
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 gnomAD v3.1." The evidence for this variant shows: it is not present in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrence of variants in the same gene." The evidence for this variant shows: no Fanconi Anemia phenotype or biallelic variants 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 as a result of in-frame deletions/insertions in a non-repeat region." The evidence for this variant shows: no change to protein length (intronic variant). 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 has been shown to be pathogenic." The evidence for this variant shows: no missense change and no pathogenic variant at the same residue. 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 assumption. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Observed co-segregation with disease in multiple affected family members (quantitative Bayes score)." 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, where missense variants are a common mechanism of disease." The evidence for this variant shows: intronic change, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Predicted splicing impact (SpliceAI ≥ 0.2) for intronic variants outside of donor/acceptor sites or damaging protein impact for missense variants." The evidence for this variant shows: no SpliceAI or other predictive splicing data available. Therefore, this criterion is not applied due to lack of computational prediction data.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Use for multifactorial likelihood clinical data with LR ≥ 2.08:1 for breast cancer phenotype." The evidence for this variant shows: no multifactorial clinical data. 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, but evidence not available for independent evaluation." The evidence for this variant shows: reported as likely benign by ClinVar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filter allele frequency above gene-specific stand-alone threshold (FAF > 0.001)." The evidence for this variant shows: absent from population, not above threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Filter allele frequency is above gene-specific strong threshold (FAF > 0.0001)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Observed in healthy individuals without recessive disease phenotype quantified by points ≥4." The evidence for this variant shows: no data on healthy homozygous individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function." The evidence for this variant shows: no functional study available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected members (LR ≤ 0.05)." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Silent substitution, missense or in-frame variant outside a clinically important domain and no splicing predicted (SpliceAI ≤ 0.1)." The evidence for this variant shows: intronic variant with no splicing prediction data. Therefore, this criterion is not applied due to missing splicing prediction.
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 fully penetrant dominant disorder." The evidence for this variant shows: no 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 deletion/insertion in repetitive region without known function." The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Missense or silent variant with no predicted impact on protein (BayesDel ≤ 0.18) and no splicing impact (SpliceAI ≤ 0.1)." The evidence for this variant shows: no BayesDel or SpliceAI data available. Therefore, this criterion is not applied due to lack of computational prediction data.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Presence of an alternate pathogenic variant explaining the phenotype in a case with no specific phenotype." The evidence for this variant shows: no such case. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but evidence not available for independent evaluation." The evidence for this variant shows: ClinVar reports likely benign from two laboratories. Therefore, this criterion is applied at Supporting strength because a reputable source classifies it as benign.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Intronic variants outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met." The evidence for this variant shows: located at -14 within motif region and BP4 not met. Therefore, this criterion is not applied.