ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5753A>G (p.His1918Arg) (rs80358804)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129155 SCV000183879 likely benign Hereditary cancer-predisposing syndrome 2017-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000113478 SCV000146690 uncertain significance Breast-ovarian cancer, familial 2 1997-11-13 no assertion criteria provided clinical testing
Color RCV000129155 SCV000903149 likely benign Hereditary cancer-predisposing syndrome 2016-07-11 criteria provided, single submitter clinical testing
Counsyl RCV000113478 SCV000786265 uncertain significance Breast-ovarian cancer, familial 2 2018-03-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000481948 SCV000591999 uncertain significance not specified 2014-04-23 criteria provided, single submitter clinical testing
GeneDx RCV000588333 SCV000565714 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5753A>G at the cDNA level, p.His1918Arg (H1918R) 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 5981A>G. This variant was observed in multiple women with breast cancer (Momozawa 2018). BRCA2 His1918Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict the creation of a novel splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 His1918Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588333 SCV000694900 uncertain significance not provided 2016-11-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5753A>G (p.His1918Arg) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/121048 (1/30303), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. A publication cites the variant indicating it is located near a predicted phosphorylation site (Tram_2013). In addition, multiple clinical diagnostic laboratories/databases cite the variant with conflicting classifications "uncertain significance" or "likely benign." One database cites the variant to co-occur with a potentially pathogenic BRCA2 variant, c.1689G>A (p.Trp563X). Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a VUS - possibly benign variant.
Invitae RCV000044744 SCV000072757 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1918 of the BRCA2 protein (p.His1918Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs80358804, ExAC 0.006%). This variant has been observed in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals it occurs with a pathogenic variant in BRCA2. While it is unknown if these variants are on the same or opposite chromosomes, this observation suggests that the c.5753A>G variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51928). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481948 SCV000600663 uncertain significance not specified 2016-12-30 criteria provided, single submitter clinical testing

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