ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1619A>T (p.Gln540Leu) (rs4988349)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131607 SCV000186623 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000222534 SCV000279288 uncertain significance not provided 2018-09-24 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1619A>T at the cDNA level, p.Gln540Leu (Q540L) at the protein level, and results in the change of a Glutamine to a Leucine (CAA>CTA). This variant was identified in one BRCA1/2 negative individual with a personal and family history of breast cancer; however it was not found in three other affected relatives (Rutter 2003). BRIP1 Gln540Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRIP1 Gln540Leu 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 Gln540Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000465039 SCV000547258 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces glutamine with leucine at codon 540 of the BRIP1 protein (p.Gln540Leu). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and leucine. This variant is present in population databases (rs4988349, ExAC 0.001%). This variant has been reported in an individual affected with breast cancer, but neither the proband’s daughter, nor her two nieces who had breast cancer carried this variant (PMID: 12872252). ClinVar contains an entry for this variant (Variation ID: 142473). 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: "Benign"; 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.
Counsyl RCV000662789 SCV000785598 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-10-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000465039 SCV000895111 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000131607 SCV000910891 likely benign Hereditary cancer-predisposing syndrome 2016-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781166 SCV000919045 uncertain significance not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1619A>T (p.Gln540Leu) variant involves the alteration of a conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 7/349872 control chromosomes (gnomAD), predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.000712 (7/9838). This frequency is about 11 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in those of Ashkenazi Jewish origin. A publication, Rutter_2003, indicates the variant was found in a Breast Cancer family, which three affected family members did not carry the variant of interest showing lack of cosegregation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance - Possibly Benign."

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