ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113478 SCV001161521 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000833
Invitae RCV001085396 SCV000072757 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129155 SCV000183879 likely benign Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481948 SCV000600663 uncertain significance not specified 2016-12-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Counsyl RCV000113478 SCV000786265 uncertain significance Breast-ovarian cancer, familial 2 2018-03-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129155 SCV000903149 likely benign Hereditary cancer-predisposing syndrome 2016-07-11 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113478 SCV000146690 uncertain significance Breast-ovarian cancer, familial 2 1997-11-13 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353529 SCV000591999 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.His1918Arg variant was not identified in the literature. This variant was identified in dbSNP (ID: rs80358804) “With untested allele”; however, frequency data was not available, thus the prevalence of this variant in the general population could not be determined. The variant was also listed in the BIC database (4X with unknown clinical importance, but it was not identified in any of the other databases searched including HGMD, LOVD, COSMIC, and UMD. The p.His1918 residue is not conserved in mammals and the variant amino acid arginine (Arg) is present in mouse, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predict the creation of a novel splice donor site at the variant nucleotide position; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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