ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5575A>G (p.Ile1859Val) (rs397507354)

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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 RCV000166864 SCV000217680 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166864 SCV000911761 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-24 criteria provided, single submitter clinical testing
GeneDx RCV000590140 SCV000321469 uncertain significance not provided 2015-07-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5575A>G at the cDNA level, p.Ile1859Val (I1859V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 5803A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile1859Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile1859Val occurs at a position that is not conserved and is located in the 6th BRC repeat domain and RAD51 binding region (Roy 2012, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ile1859Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590140 SCV000694881 uncertain significance not provided 2017-03-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5575A>G (p.Ile1859Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 120450 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. The variant is located in one of the BRCA repeats that is critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment (IPR002093). However, because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000229983 SCV000283266 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1859 of the BRCA2 protein (p.Ile1859Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. 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: 37974). 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 valine 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 RCV000254807 SCV000600646 uncertain significance not specified 2017-01-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590140 SCV000887848 uncertain significance not provided 2017-11-22 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031555 SCV000054160 uncertain significance Breast-ovarian cancer, familial 2 2010-09-22 no assertion criteria provided clinical testing

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