ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3224C>T (p.Ser1075Leu) (rs183928474)

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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 RCV000220966 SCV000276213 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ;In silico models in agreement (benign)
GeneDx RCV000254825 SCV000321486 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3224C>T at the cDNA level, p.Ser1075Leu (S1075L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRIP1 Ser1075Leu was not observed 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Ser1075Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000458321 SCV000547317 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1075 of the BRIP1 protein (p.Ser1075Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs183928474, ExAC 0.009%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 232157). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Counsyl RCV000662888 SCV000785802 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-12-05 criteria provided, single submitter clinical testing
Color RCV000220966 SCV000911408 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-21 criteria provided, single submitter clinical testing

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