Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000044725 | SCV000072738 | likely benign | Hereditary breast ovarian cancer syndrome | 2023-12-07 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000130620 | SCV000185496 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-23 | criteria provided, single submitter | clinical testing | 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 alteration was observed in 0/7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also detected in 2/11,386 Chinese Han individuals undergoing routine health examinations and screened for BRCA1/2 alterations (Dong H et al. J Med Genet, 2021 08;58:565-569). Authors of one study classified this variant as likely not pathogenic based on a combination of multifactorial likelihood analyses and an in vitro splicing assay and another study using four in silico prediction tools found this variant to be tolerated in all models (Whiley PJ et al. PLoS One, 2014 Jan;9:e86836; Ernst C et al. BMC Med Genomics, 2018 03;11:35). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV000479143 | SCV000569646 | uncertain significance | not provided | 2018-02-22 | criteria provided, single submitter | clinical testing | 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. |
Color Diagnostics, |
RCV000130620 | SCV000903958 | likely benign | Hereditary cancer-predisposing syndrome | 2016-12-19 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002281732 | SCV002571081 | uncertain significance | not specified | 2023-05-15 | criteria provided, single submitter | clinical testing | 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. |
University of Washington Department of Laboratory Medicine, |
RCV000130620 | SCV003849039 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
All of Us Research Program, |
RCV000113466 | SCV004846631 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2023-09-17 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000479143 | SCV005624469 | uncertain significance | not provided | 2024-02-21 | criteria provided, single submitter | clinical testing | 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. |
Breast Cancer Information Core |
RCV000113466 | SCV000146673 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2002-05-29 | no assertion criteria provided | clinical testing |