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 (LOF) is a known mechanism of disease." The evidence for this variant shows: it is a missense change (H114R), not a null variant. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
PS1 (Not Applied)
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 (SpliceAI≤0.1))." The evidence for this variant shows: no other variant at codon 114 has been classified as pathogenic. Therefore, this criterion is not applied because there is no known pathogenic variant causing the same amino acid change.
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." The evidence for this variant shows: no information on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo data.
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 as measured by effect on protein or mRNA transcript." The evidence for this variant shows: no functional studies have been reported. Therefore, this criterion is not applied because functional impact has not been tested.
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 (p-value ≤0.05 and OR ≥4)." The evidence for this variant shows: no case-control or enrichment data. Therefore, this criterion is not applied due to absence of case-control evidence.
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 evidence for this variant shows: H114 is outside the defined BRCA2 PALB2 binding domain (aa10-40) and DNA binding domain (aa2481-3186). Therefore, this criterion is not applied because the residue is not in a critical domain.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Absent from controls in an outbred population, from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer." The evidence for this variant shows: it is present in gnomAD at MAF 0.0108%. Therefore, this criterion is not applied because the variant is not absent in population databases.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA-related Fanconi Anemia and co-occurring variants." The evidence for this variant shows: no Fanconi Anemia phenotype or biallelic data. 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 deletions/insertions or stop-loss variants." The evidence for this variant shows: it is a missense substitution with no change in protein length. 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 pathogenic missense change has been seen before." The evidence for this variant shows: no other pathogenic missense variant reported at residue H114. 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 and maternity." The evidence for this variant shows: no de novo assessment. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Strong: Co-segregation with disease in multiple affected family members (LR ≥18.7:1)." The evidence for this variant shows: no segregation data. 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 pathogenic missense variants are common." The evidence for this variant shows: BRCA2 has many missense of uncertain effect. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting: Apply for missense inside a functional domain with BayesDel no-AF ≥0.30 or for predicted splicing impact (SpliceAI ≥0.2)." The evidence for this variant shows: BayesDel score is benign and SpliceAI = 0.03. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Use phenotype-based multifactorial likelihood data for BRCA-related cancer (LR thresholds)." The evidence for this variant shows: no multifactorial clinical data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar entries include VUS and likely benign, no consensus pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Filter allele frequency (FAF) >0.1% in gnomAD non-cancer." The evidence for this variant shows: MAF = 0.0108%, below the 0.1% threshold. 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." The evidence for this variant shows: MAF = 0.0108% (>0.01%). Therefore, this criterion is applied at Strong strength because the allele frequency exceeds the benign threshold.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: Applied in absence of Fanconi Anemia phenotype (BS2 ≥4 points)." The evidence for this variant shows: no clinical FA data. 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." The evidence for this variant shows: no functional assays. 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 ≤0.05:1)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, the rule for BP1 is: "Strong: Apply BP1_Strong for missense variants outside a functional domain and no predicted splicing impact (SpliceAI ≤0.1)." The evidence for this variant shows: residue H114 is outside known functional domains and SpliceAI = 0.03. Therefore, this criterion is applied at Strong strength because the variant is outside a critical domain with no splicing impact predicted.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in a repetitive region without functional constraint." The evidence for this variant shows: it is a missense substitution, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense inside a functional domain with BayesDel no-AF ≤0.18 and SpliceAI ≤0.1." The evidence for this variant shows: it is outside functional domains. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Strong: Use to capture combined LR against pathogenicity based on multifactorial clinical data." The evidence for this variant shows: no co-observation clinical data. 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 evidence." The evidence for this variant shows: ClinVar entries are VUS and likely benign, no unanimous benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Silent/intronic variants inside or outside domains if BP4 met." The evidence for this variant shows: it is a missense substitution. Therefore, this criterion is not applied.