BRCA2 c.632-5T>C, p.?
NM_000059.4:c.632-5T>C
Variant of Uncertain Significance (VUS)
This intronic variant (c.632-5T>C) is absent from population databases (PM2_Supporting) but lies outside canonical splice sites and lacks functional or segregation evidence. Computational splicing prediction (SpliceAI 0.18) does not meet VCEP thresholds. No further benign or pathogenic criteria are met, and the variant remains classified as VUS.
ACMG/AMP Criteria Applied
PM2
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.632-5T>C
Protein Change
?
Location
Exon 7
(Exon 7 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.632-5T>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 2 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
1 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 (1 clinical laboratories) and 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.85
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 loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows it is an intronic alteration at c.632-5, which is outside the canonical splice site positions +/-1,2. Therefore, this criterion is not applied because the variant does not affect a canonical splice site.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no change to an amino acid and no previously established pathogenic variant at this splice region. 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." There is no evidence of a confirmed de novo occurrence for this variant. 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." No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls (p-value ≤0.05 and OR ≥4)." There are no case-control or segregation data demonstrating enrichment of this variant in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, there is no specific PM1 provision for BRCA2 beyond standard hotspot/domain definitions, and this variant lies in an intronic region outside known functional domains. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Absent from controls in an outbred population (gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer) with sufficient coverage." The evidence for this variant shows it is not present in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength because the variant is absent from large population datasets.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 applies only for BRCA1/2-related Fanconi Anemia cases with co-occurring variants in the same gene. There is no clinical phenotype or co-occurrence data for Fanconi Anemia. 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 deletions/insertions in a non-repeat region or stop-loss variants." This variant does not alter protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "A novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." This is an intronic variant, not a missense change. Therefore, PM5 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." There is no evidence of de novo occurrence. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 co-segregation criteria require quantitative segregation data in multiple affected family members. No segregation data are available for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." This is an intronic variant and not a missense change. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 (Supporting) for splicing is: "Predicted splicing impact (SpliceAI ≥0.2)." The SpliceAI maximum score for this variant is 0.18, below the 0.2 threshold. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 is used only with multifactorial likelihood models for BRCA-associated cancer phenotypes. No such multifactorial data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is: "Reputable source reports variant as pathogenic without available evidence." ClinVar submissions are conflicting (Likely Benign and VUS). Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 (Stand Alone) is: "Filter allele frequency (FAF) above 0.1% in non-founder populations." This variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 (Strong) is: "Filter allele frequency above 0.01% in non-founder populations." This variant is absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies in the absence of Fanconi Anemia features in individuals homozygous or compound heterozygous for BRCA2 variants. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 (Strong) requires well-established functional studies showing no damaging effect. No functional studies have been conducted. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected family members with quantitative analysis. No segregation data exist. Therefore, BS4 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 splicing impact. This is an intronic variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis for recessive." No such co-observation data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is: "In-frame indels in repetitive regions without a known function." This is not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 (Supporting) for intronic variants is: "Outside donor/acceptor sites and SpliceAI ≤0.1." The SpliceAI score for this variant is 0.18, above the 0.1 threshold. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 is used in multifactorial analyses for co-occurrence with pathogenic variants in different genes. No such data exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is: "Reputable source reports variant as benign without evidence." ClinVar submissions are conflicting. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants outside conserved positions (+7/–21) if BP4 is met. This variant is at –5, not beyond –21, and BP4 is not met. Therefore, BP7 is not applied.