ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3772A>G (p.Ile1258Val) (rs587782720)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132209 SCV000187291 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000132209 SCV000683580 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
GeneDx RCV000657047 SCV000567590 uncertain significance not provided 2017-06-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3772A>G at the cDNA level, p.Ile1258Val (I1258V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 4000A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile1258Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile1258Val occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). While protein-based in silico analyses predict that this variant is unlikely to alter protein structure or function, multiple splicing models predict that this variant may be associated with a gain of a strong cryptic splice donor site for intron 11 and lead to abnormal splicing. 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 Ile1258Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000465587 SCV000549835 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1258 of the BRCA2 protein (p.Ile1258Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs587782720, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142792). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000486148 SCV000600562 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657047 SCV000887797 uncertain significance not provided 2018-08-05 criteria provided, single submitter clinical testing

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