ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2167G>A (p.Val723Ile) (rs145616741)

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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 RCV000222035 SCV000274021 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000222035 SCV000903709 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000222292 SCV000278900 uncertain significance not provided 2015-11-17 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2167G>A at the cDNA level, p.Val723Ile (V723I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Val723Ile was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Val723Ile occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Val723Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000636157 SCV000757589 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 723 of the BRIP1 protein (p.Val723Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 230464). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably 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.

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