ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.413T>C (p.Leu138Ser) (rs587780251)

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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 RCV000116160 SCV000183884 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116160 SCV000689391 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Counsyl RCV000662431 SCV000784887 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-01-25 criteria provided, single submitter clinical testing
GeneDx RCV000212301 SCV000150069 uncertain significance not provided 2018-07-24 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.413T>C at the cDNA level, p.Leu138Ser (L138S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). This variant has been identified in 1/13,213 cases and 2/5,242 controls in a breast cancer case-control study, as well as in one individual with a history of a Lynch-related cancer and/or polyps (Yurgelun 2015, Easton 2016). BRIP1 Leu138Ser 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Leu138Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168359 SCV000219049 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 138 of the BRIP1 protein (p.Leu138Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs587780251, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer, B-cell acute lymphoblastic leukemia, and suspected Lynch syndrome, as well as in two unaffected control individuals (PMID: 25980754, 26580448, 26921362). ClinVar contains an entry for this variant (Variation ID: 128191). 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: "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.

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