ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.373A>G (p.Ile125Val) (rs587776489)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221601 SCV000276809 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-24 criteria provided, single submitter clinical testing
GeneDx RCV000484624 SCV000564713 uncertain significance not provided 2015-02-12 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.373A>G at the cDNA level, p.Ile125Val (I125V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). Using alternate nomenclature, this variant would be defined as BRCA1 492A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile125Val 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. BRCA1 Ile125Val occurs at a position that is conserved across species and is not located in a known functional domain. 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 BRCA1 Ile125Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000814140 SCV000954541 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 125 of the BRCA1 protein (p.Ile125Val). 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 BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 156193). 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: "Possibly 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.
Sharing Clinical Reports Project (SCRP) RCV000144210 SCV000189283 uncertain significance Breast-ovarian cancer, familial 1 2011-05-12 no assertion criteria provided clinical testing

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