BRCA2 c.996T>G, p.Ile332Met
NM_000059.4:c.996T>G
COSMIC ID: COSM274156
Variant of Uncertain Significance (VUS)
BRCA2 c.996T>G (p.I332M) remains a Variant of Uncertain Significance based on absence from controls (PM2_Supporting) and benign computational evidence in non-domain region (BP1_Strong) with no additional supporting or conflicting data.
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.996T>G
Protein Change
I332M
Location
Exon 10
(Exon 10 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 332: I332V, I332T, I332N
Alternate Identifiers
COSM274156
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.996T>G
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
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
ClinVar reports other pathogenic variants at position 332: I332V, I332T, I332N
PM5 criterion applied.
Functional Summary
The BRCA2 I332M variant has not been functionally characterized. In silico studies provide inconclusive evidence regarding its effect on protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.201
0.201
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: 1.24metasvm: Tmetalr: Tprimateai: 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 (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 a missense change (I332M), 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 (no confirmed or predicted effect on mRNA splicing)." The evidence for this variant shows no previously established pathogenic variant with the same amino acid change (I332M). 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 are no data on de novo occurrence for this variant. 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." No functional studies exist for BRCA2 I332M. 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)." No case-control data are available for this variant. 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 critical functional domain without benign variation." The I332M change lies outside of defined BRCA2 functional domains (PALB2-binding aa10–40 and DNA-binding aa2481–3186). 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 (non-cancer)." The evidence for this variant shows it is absent from 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 BRCA1/2-related Fanconi Anemia phenotype with co-occurring variants, based on point system." No Fanconi Anemia phenotype or co-occurrence data are available. 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." This variant is a single amino acid substitution without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 applies only to protein termination codon (PTC) variants in exons with known PTC pathogenic variants. I332M is a missense variant, not a PTC. 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 without confirmation of paternity/maternity." 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: "Supporting: Co-segregation with disease in multiple affected family members." No family 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 low rate of benign missense variation where missense variants are a common mechanism of disease." BRCA2 has a high rate of both pathogenic and benign missense variants. 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)." The evidence shows SpliceAI=0 and BayesDel no-AF unknown but in silico mixed; criteria for PP3 are not met. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Use only to capture combined LR toward pathogenicity based on phenotype specificity." No specific phenotype or multifactorial likelihood 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 with pathogenic classification but without available evidence." No such source exists for this variant. 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 >0.1% in gnomAD." This variant is absent from population databases. 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." This variant is absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Applied in absence of recessive disease features (Fanconi Anemia) in healthy individuals." No data on healthy adult carriers are available. 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." No functional studies exist. 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." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong: Apply BP1_Strong for silent substitution, missense or in-frame indels outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." The I332M change is a missense variant at residue 332, outside defined functional domains (aa10–40 and 2481–3186), with SpliceAI=0 predicting no splicing impact. Therefore, this criterion is applied at Strong strength.
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 gene." No trans co-occurrence data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP3 is: "Strong for in-frame indels in repetitive regions without known function." This variant is a missense change, 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 variants inside a functional domain with no predicted impact via protein change (BayesDel ≤0.18) and no splicing (SpliceAI ≤0.1)." The I332M variant lies outside functional domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Use only to capture combined LR against pathogenicity based on multifactorial likelihood in co-observed cases." No such data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source with benign classification but without evidence." No such source exists. 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 outside conserved splice sites with no splicing impact, OR missense inside domain if BS3 met." This variant is missense outside domain and BS3 is not met. Therefore, this criterion is not applied.