ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5470A>G (p.Ile1824Val) (rs587782026)

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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 RCV000130459 SCV000185324 uncertain significance Hereditary cancer-predisposing syndrome 2013-10-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130459 SCV000683323 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765356 SCV000896621 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000481196 SCV000566784 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5470A>G at the cDNA level, p.Ile1824Val (I1824V) 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 5589A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile1824Val was not observed 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. BRCA1 Ile1824Val occurs at a position that is not conserved and is located in the BRCT 2 domain as well as a region known to interact with multiple other proteins (UniProt, Paul 2014). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may create a new cryptic splice acceptor site and possibly 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 BRCA1 Ile1824Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168345 SCV000219034 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1824 of the BRCA1 protein (p.Ile1824Val). The isoleucine residue is highly 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: 141804). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not available"; Align-GVGD: "Class C0"). 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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