ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3172A>G (p.Ile1058Val) (rs1064795478)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479949 SCV000571315 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3172A>G at the cDNA level, p.Ile1058Val (I1058V) 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 BRCA1 3291A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Ile1058Val was not observed in large population cohorts (Lek 2016). This variant is located in the DNA Binding domain and the RAD51 binding domain (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Ile1058Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571167 SCV000665909 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000571167 SCV000912150 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing
Invitae RCV001212358 SCV001383941 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1058 of the BRCA1 protein (p.Ile1058Val). 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 BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 421966). 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.

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