ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4297A>G (p.Ile1433Val) (rs541512953)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166435 SCV000217230 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000486992 SCV000564742 uncertain significance not provided 2016-11-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4297A>G at the cDNA level, p.Ile1433Val (I1433V) 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 BRCA1 4416A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile1433Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ile1433Val occurs at a position that is not conserved and is located in the SCD domain and region that binds multiple other proteins. (Chen 1998, Narod 2004, Clark 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 create a strong cryptic splice donor site upstream of the natural splice donor site 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 information, it is unclear whether BRCA1 Ile1433Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000539071 SCV000635963 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1433 of the BRCA1 protein (p.Ile1433Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs541512953, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 186786). 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. 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.

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