ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1721C>T (p.Pro574Leu) (rs377302300)

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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 RCV000562779 SCV000668893 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000562779 SCV000684154 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
GeneDx RCV000484019 SCV000564813 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1721C>T at the cDNA level, p.Pro574Leu (P574L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRIP1 Pro574Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Pro574Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230474 SCV000290987 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 574 of the BRIP1 protein (p.Pro574Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs377302300, ExAC 0.03%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 241630). 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: "Deleterious"; 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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