BRCA2 c.3824T>C, p.Ile1275Thr
NM_000059.4:c.3824T>C
Variant of Uncertain Significance (VUS)
This BRCA2 I1275T variant is a rare missense change outside key functional domains. It meets PM2_Supporting for rarity and BP1_Strong for benign computational/splicing predictions. No additional pathogenic or benign evidence is available, resulting in a final classification of Variant of Uncertain Significance.
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.3824T>C
Protein Change
I1275T
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1275 in gene BRCA2
Variant interpretation based on transcript NM_000059.4
Genome Browser
Loading genome browser...
HGVS InputNM_000059:c.3824T>C
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.000458%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000977%
Very Rare
Global: 0.000458%
European (non-Finnish): 0.000977%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 218466Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000458%, 1/218466 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000977%, 1/102406 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
8 publications
Uncertain Significance (VUS)
Based on 11 submitter reviews in ClinVar
Submitter Breakdown
11 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (8)
Variant summary: BRCA2 c.3824T>C (p.Ile1275Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-06 in 218466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3824T>C has been reported in the literature in an individual affected with breast cancer (D'Argenio_2015) and in an individual affected with lung adenocarcinoma without strong evidence for or against pathogenicity (Parry_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported (BRCA1 c.3770_3771delAG, p.Glu1257Glyfs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This missense variant replaces isoleucine with threonine at codon 1275 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and three unaffected individuals (PMID: 25896959, 33471991; Leiden Open Variation Database DB-ID BRCA2_001200). This variant has been identified in 1/218466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
The BRCA2 c.3824T>C (p.Ile1275Thr) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 25896959 (2015)) and lung cancer (PMID: 28843361 (2017)). In addition, this variant has been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000098 (1/102406 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (11 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
No evidence of other pathogenic variants at position 1275 in gene BRCA2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.198
0.198
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: -0.38polyphen_prediction: benignmetasvm: 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 PVS1 rule 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 a missense change (I1275T), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule 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 (SpliceAI ≤ 0.1))." There is no previously established pathogenic variant causing the same I1275T change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS2 rule 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. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the PS3 rule is: "Strong Well-established in vitro or in vivo functional studies supportive of 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, the PS4 rule is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (OR ≥ 4, p ≤ 0.05)." No case-control data exist for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the PM1 rule involves variants within clinically important functional domains (BRCA2 PALB2 binding aa 10–40 or DNA binding aa 2481–3186). I1275 lies outside these regions. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the PM2 rule is: "Supporting Absent from controls in an outbred population, from gnomAD v2.1 and v3.1 (non-cancer)." The variant is extremely rare (MAF=0.000458%, gnomAD non-cancer) and meets coverage criteria. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the PM3 rule is: "Apply for patients with phenotype consistent with BRCA1/2-related Fanconi Anemia and co-occurrence of variants in the same gene." No Fanconi Anemia phenotype or co-occurring variants are reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM4 rule is: "Protein length changes due to in-frame deletions/insertions." This is a missense substitution without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP and standard ACMG guidelines, the PM5 rule is: "Novel missense change at an amino acid residue where a different missense change has been established as pathogenic." No other pathogenic variant at codon 1275 is reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity." No such data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the PP1 rule is: "Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP2 rule is: "Missense in a gene with a low rate of benign missense variants and where missense is a common mechanism of disease." BRCA2 has many benign and pathogenic missense variants; insufficient evidence to apply. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the PP3 rule is: "Supporting Apply PP3 for missense variants inside a clinically important functional domain with predicted impact (BayesDel no-AF ≥ 0.30 or SpliceAI ≥ 0.2)." This variant lies outside domains and has no pathogenic computational predictions. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the PP4 rule is: "Use only for multifactorial likelihood data in breast cancer phenotypes." No such data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP5 rule is: "Reputable source reports variant as pathogenic." ClinVar submissions list this variant as VUS. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the BA1 rule is: "Stand Alone FAF > 0.001 in gnomAD v2.1/v3.1 non-cancer." The variant frequency (0.000458%) is below this threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the BS1 rule is: "Strong Filter allele frequency (FAF) > 0.0001 in gnomAD v2.1/v3.1 non-cancer." The variant frequency is 0.00000458 in gnomAD non-cancer, below the threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the BS2 rule is: "Observation in healthy adult without FA phenotype (points-based)." No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the BS3 rule is: "Strong Well-established functional studies show no damaging effect." No functional studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the BS4 rule 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 BP1 rule is: "Strong Apply BP1_Strong for missense variants outside clinically important functional domains AND no splicing predicted (SpliceAI ≤ 0.1)." I1275 lies outside defined domains and SpliceAI predicts no splicing impact (score=0). Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP2 rule is: "Observed in trans with a pathogenic variant for a dominant disorder." No such data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, the BP3 rule pertains to in-frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the BP4 rule is: "Supporting Missense variants inside a clinically important domain with no predicted impact (BayesDel ≤ 0.18 AND SpliceAI ≤ 0.1)." This variant lies outside those domains. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the BP5 rule is: "Cases with two pathogenic variants in different genes with no specific phenotype." Not applicable to this variant. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP6 rule is: "Reputable source reports variant as benign." No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the BP7 rule is: "Strong for silent/intronic variants; Supporting for intronic/silent inside domains if BP4 met." This variant is missense. Therefore, this criterion is not applied.