ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6688A>G (p.Ile2230Val) (rs587779366)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130830 SCV000185727 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130830 SCV000683796 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000586574 SCV000108634 uncertain significance not provided 2015-09-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6688A>G at the cDNA level, p.Ile2230Val (I2230V) 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 6916A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile2230Val 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 Ile2230Val occurs at a position that is not conserved through species and is not located in a known functional domain (Borg 2010, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ile2230Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586574 SCV000694985 uncertain significance not provided 2016-01-19 criteria provided, single submitter clinical testing Variant summary: The c.6688A>G in BRCA2 gene is a missense variant involves a conserved nucleotide and 3/4 in silico tools predict benign outcome. This variant is not present in the control population dataset of ExAC, suggesting this variant is not a common polymorphism. The variant is not reported in the literature, however, was found to co-occur with a deleterious variant, c.2457delC in BRCA1 gene in individual referred for genetic testing (internal LCA data). In addition, the variant was classified as VUS by several reputable clinical laboratories/diagnostic centers. Taken together, the variant was classified as Variant of Uncertain until more information becomes available.
Invitae RCV000474506 SCV000549757 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2230 of the BRCA2 protein (p.Ile2230Val). The isoleucine residue is moderately 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: 89052). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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