ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5747A>G (p.His1916Arg) (rs431825334)

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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 RCV000214692 SCV000277494 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761129 SCV000891045 uncertain significance Acute myeloid leukemia 2016-12-07 no assertion criteria provided clinical testing
Color RCV000214692 SCV000905800 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763890 SCV000894825 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000160100 SCV000210369 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5747A>G at the cDNA level, p.His1916Arg (H1916R) 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 5975A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 His1916Arg was not observed 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. Based on currently available evidence, it is unclear whether BRCA2 His1916Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779974 SCV000916947 uncertain significance not specified 2018-04-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5747A>G (p.His1916Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 276448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no germline occurrence of c.5747A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been identified in our laboratory (BRCA1 c.5193+1G>T), providing supporting evidence for a benign role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000702374 SCV000831226 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1916 of the BRCA2 protein (p.His1916Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 96828). 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. 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 RCV000160100 SCV000889077 uncertain significance not provided 2018-01-17 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082949 SCV000115023 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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