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 for PVS1: "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 that it is a missense substitution (H114R), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines for PS1: "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))." The evidence for this variant shows no prior pathogenic variant at residue H114, and no supported splicing change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines for PS2: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no information on de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines for PS3: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." There are no functional studies for BRCA2 H114R. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines for PS4: "Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (case-control studies; p-value ≤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 for PM1: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The H114R substitution lies outside known BRCA2 functional domains (aa10-40 and aa2481-3186). Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines for PM2 (Supporting): "Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." This variant is observed in gnomAD at MAF=0.0108%. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines for PM3: "Strong Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurring variants in the same gene." There is no evidence of Fanconi Anemia phenotype or biallelic variants. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The H114R change does not alter protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: "Strong Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." H114R is a missense change, not a termination codon. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6: "Assumed de novo, without confirmation of paternity and maternity." There is no de novo information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines for PP1: "Strong Co-segregation with disease in multiple affected family members..." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." BRCA2 has both benign and pathogenic missense variants; no specific low benign rate applies. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PP3: "Supporting Apply PP3 for missense or in-frame variants inside a clinically important functional domain with BayesDel no-AF score ≥0.30, or predicted splicing impact (SpliceAI ≥0.2)." H114R is outside defined domains and SpliceAI=0.03. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines for PP4: "Strong Use only to capture combined LR based on multifactorial likelihood clinical data." No multifactorial or phenotypic data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5: "Reputable source reports variant as pathogenic without available evidence." This variant is reported as VUS or likely benign in ClinVar. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: "Stand Alone FAF >0.1% (FAF >0.001) in gnomAD." The variant MAF=0.0108% (0.000108) is below 0.1%. Therefore, this criterion is not applied.
BS1 (Strong)
According to VCEP guidelines for BS1: "Strong Filter allele frequency (FAF) is above 0.01% (FAF >0.0001) in gnomAD." The variant MAF=0.0108% (0.000108) exceeds the 0.0001 threshold. Therefore, this criterion is applied at Strong strength.
BS2 (Not Applied)
According to VCEP guidelines for BS2: "Strong Applied in absence of features of recessive disease (Fanconi Anemia)." There is no evidence of homozygous or FA phenotype. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Strong Well-established functional studies show no damaging effect on protein function." No functional data demonstrating lack of effect are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines for BS4: "Strong Lack of segregation in affected members..." No segregation studies are available. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines for BP1_Strong: "Apply BP1_Strong for missense variants outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." H114R is at residue 114 outside domains aa10-40 and aa2481-3186, with SpliceAI=0.03. Therefore, this criterion is applied at Strong strength.
BP2 (Not Applied)
According to standard ACMG guidelines for BP2: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene." No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3: "In-frame deletions/insertions in a repetitive region without a known function." This is a missense variant, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines for BP4: "Supporting Missense variants inside a functional domain with no predicted impact (BayesDel no-AF ≤0.18 and SpliceAI ≤0.1)." H114R lies outside defined domains. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines for BP5: "Use only to capture LR against pathogenicity based on co-observation with pathogenic variants in other genes." No such co-observations are reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines for BP6: "Reputable source reports variant as benign without available evidence." The variant is classified as VUS or likely benign in ClinVar with conflicting submissions. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines for BP7: "Silent or intronic variants outside conserved splice sites with no predicted impact." This is a missense variant. Therefore, this criterion is not applied.