ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6269A>G (p.His2090Arg) (rs397507366)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562031 SCV000665106 likely benign Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Color Health, Inc RCV000562031 SCV000688972 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter clinical testing This missense variant replaces histidine with arginine at codon 2090 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 32994724). This variant has been identified in 1/244318 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000031611 SCV000784901 uncertain significance Breast-ovarian cancer, familial 2 2017-02-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175040 SCV001338562 uncertain significance not specified 2020-04-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6269A>G (p.His2090Arg) 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 4.1e-06 in 244318 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 occurrence of c.6269A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001214226 SCV001385899 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 2090 of the BRCA2 protein (p.His2090Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs397507366, ExAC 0.002%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 38030). 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 RCV001284435 SCV001470232 uncertain significance not provided 2019-10-18 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031611 SCV000054218 uncertain significance Breast-ovarian cancer, familial 2 2012-02-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354947 SCV001549679 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing BRCA2, EXON11, c.6269A>G, p.His2090Arg, Heterozygous, Uncertain SignificancernThe BRCA2 p.His2090Arg variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs397507366) as “with likely benign allele”, ClinVar (classified as uncertain significance by Color, Counsyl and SCRP; and as likely benign by Ambry Genetics) and LOVD 3.0 (observed 1X). The variant was identified in control databases in 1 of 239,480 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 1 of 109,466 chromosomes (freq: 0.000009); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His2090 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 uncertain significance. Assessment Date: 2019/07/23.

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