ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.386C>T (p.Pro129Leu) (rs587780831)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123359 SCV000166682 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 129 of the BRIP1 protein (p.Pro129Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs587780831, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 136150). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000213973 SCV000273830 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000484573 SCV000567644 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.386C>T at the cDNA level, p.Pro129Leu (P129L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Pro129Leu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Pro129Leu occurs at a position that is not conserved and is not located in a functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Pro129Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000213973 SCV000912130 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing

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