Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000059.4 | MANE Select | 11954 nt | 200–10456 |
| NM_000059.2 | Alternative | 11386 nt | 228–10484 |
| NM_000059.3 | RefSeq Select | 11386 nt | 228–10484 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis missense variant replaces histidine with arginine at codon 114 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 (PMID: 19491284) and in a breast cancer case-control meta-analysis in 5/60463 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001948). A multifactorial analysis also has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.5618, respectively (PMID: 31131967). This variant has been identified in 27/251014 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.
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
The BRCA2 c.341A>G (p.His114Arg) variant has been reported in the published literature in breast cancer cases (PMIDs: 33471991 (2021), 37060015 (2023)), including early-onset (PMID: 19491284 (2009)), as well as reportedly healthy individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00054 (14/25950 chromosomes in Swedish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
This missense variant replaces histidine with arginine at codon 114 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 19491284, 37060015), and it has been detected in a breast cancer case-control meta-analysis in 5/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001948). Multifactorial analyses have reported likelihood ratios (LRs) reaching a combined LR = 0.5302 based on personal and family history for 4 carriers and co-occurrence with a pathogenic variant (PMID: 31131967, 31853058). This variant has been identified in 27/251014 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.
Variant summary: BRCA2 c.341A>G (p.His114Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00011 in 251014 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for disease-causing variants in BRCA2, allowing no conclusion about variant significance. c.341A>G has been observed in individual(s) affected with Hereditary Breast And Ovarian Cancer Syndrome and melanomas (Haffty_AO_2009). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases and 4/53461 controls (Dorling_2021 through LOVD). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19491284, 40072281, 37060015, 33471991). ClinVar contains an entry for this variant (Variation ID: 51460). Based on the evidence outlined above, the variant was classified as uncertain significance.
"This variant has been reported in ClinVar as Uncertain Significance (1 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain significance (6 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -442 bp |
| Donor Loss (DL) | 0.0 | -24 bp |
| Acceptor Gain (AG) | 0.03 | -20 bp |
| Donor Gain (DG) | 0.0 | 84 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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 is a known mechanism of disease." The evidence for this variant shows it is a missense change (p.H114R), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "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)." There is no evidence of a previously established pathogenic variant causing the same amino acid change (H114R). Therefore, this criterion is not applied.
PS2 (Not Applied)
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 demonstrating a confirmed de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." There are no functional studies for BRCA2 p.H114R demonstrating a damaging effect. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control studies; p≤0.05 and OR≥4)." No case-control data are available for this variant. Therefore, this criterion is not applied.
PM1 (Not Applied)
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 p.H114R change lies outside known BRCA2 functional domains (PALB2-binding aa 10–40; DNA-binding aa 2481–3186). Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent from controls in gnomAD v2.1 and v3.1 (non-cancer)." The variant is present in gnomAD at MAF = 0.0108%. Therefore, PM2 is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Supporting Apply for patient with phenotype consistent with BRCA-related Fanconi Anemia and co-occurring variants." There is no Fanconi Anemia phenotype or co-occurring BRCA2 variants reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The p.H114R change is a missense substitution with no length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is established as pathogenic." No other pathogenic missense alterations at codon 114 have been reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity/maternity." There are no data on assumed de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members." There are no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." BRCA2 has numerous benign and pathogenic missense variants; there is no specific evidence to support PP2. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Apply PP3 for missense or in-frame variants inside a clinically important functional domain with predicted impact (BayesDel ≥0.30) or predicted splicing (SpliceAI ≥0.2)." The p.H114R variant lies outside defined functional domains and computational tools predict no deleterious impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting Use phenotype specificity and multifactorial likelihood clinical data (LR ≥2.08)." No specific multifactorial or phenotype data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic without accessible evidence." ClinVar submissions for this variant are VUS or Likely Benign, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone FAF >0.1% in gnomAD non-cancer populations." The variant MAF is 0.0108% (<0.1%). Therefore, this criterion is not applied.
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: "Strong Filter allele frequency (FAF) >0.01% in gnomAD non-cancer populations." The variant MAF is 0.0108% (>0.01%). Therefore, BS1 is applied at Strong strength.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Applied in absence of features of recessive disease (Fanconi Anemia)." There are no phenotyped healthy individuals confirmed to lack FA features. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established functional studies show no damaging effect." No functional assays demonstrating no impact are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected family members (LR ≤0.05)." No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: "Strong Silent substitution or missense outside functional domains with no splicing predicted." The variant is missense but lies outside a defined functional domain; however BP1 is reserved for silent changes outside domains. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observation of variant in trans with a pathogenic variant or in cis with a pathogenic variant in healthy individuals." No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive regions without a known function." The variant is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting Missense or in-frame variants inside a functional domain with no predicted impact, or silent/intronic variants with no splicing impact." The p.H114R variant lies outside functional domains. Standard computational tools predict no effect but VCEP BP4 does not apply outside domains. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Strong Use when variant co-occurs with pathogenic variants in other breast–ovarian cancer genes with no specific phenotype." No co-occurrence data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without accessible evidence." ClinVar submissions are VUS or Likely Benign, which do not meet the threshold for BP6. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Silent or intronic variants outside conserved splice sites with no predicted impact." The p.H114R change is a missense variant, not silent or intronic. Therefore, this criterion is not applied.