NM_000059.4:c.5714A>G
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):c.5714A>G(p.His1905Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1905N) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5714A>G | p.His1905Arg | missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.5345A>G | p.His1782Arg | missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.5714A>G | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 33 show subpopulations
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461570Hom.: 0 Cov.: 45 AF XY: 0.00000413 AC XY: 3AN XY: 727086 show subpopulations
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74368 show subpopulations
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
The p.H1905R variant (also known as c.5714A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5714. The histidine at codon 1905 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
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not provided Uncertain:2
The BRCA2 c.5714A>G (p.His1905Arg) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)) as well as reportedly healthy individuals (PMID: 32467295 (2020), 30287823 (2018)). This variant is described 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, 0.000013 (2/152224 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. -
This variant is denoted BRCA2 c.5714A>G at the cDNA level, p.His1905Arg (H1905R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 5942A>G. BRCA2 His1905Arg was classified as likely not pathogenic by a multifactorial likelihood analysis utilizing bioinformatic models and segregation data (Whiley 2014). BRCA2 His1905Arg was not observed in large population databases (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 His1905Arg is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 His1905Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
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not specified Uncertain:1
Variant summary: BRCA2 c.5714A>G (p.His1905Arg) 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 1.1e-05 in 271460 control chromosomes (gnomAD and publications).The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5714A>G has been identified as a VUS in a screen of healthy individuals from a Han Chinese population (found in 2/9,331 individuals) and in a case-control study of Japanese breast cancer patients where it was not found in cases but was found in controls (Momozawa_2018, Dong_2020). To our knowledge, no occurrence of in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported in the literature. The variant has been classified as IARC Class 2 (likely not pathogenic) based on multifactorial likelihood analysis (Whiley_2014) however, this has yet to be confirmed by functional studies. The following publications have been ascertained in the context of this evaluation (PMID: 24489791, 30287823, 32467295). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (likely benign n=3, VUS n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at