ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2233G>A (p.Ala745Thr) (rs587780235)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116137 SCV000186759 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116137 SCV000537547 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000662754 SCV000785542 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000586157 SCV000150046 uncertain significance not provided 2018-04-19 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2233G>A at the cDNA level, p.Ala745Thr (A745T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has been observed in several individuals with a personal and/or family history of breast cancer (Catucci 2012, Easton 2016, Maxwell 2016, Weber-Lassalle 2018), as well as in 1/3,236 ovarian cancer cases, and not observed in 3,431 unaffected controls (Ramus 2015). BRIP1 Ala745Thr was observed at an allele frequency of 0.09% (9/9,844) in individuals of Ashkenazi Jewish ancestry 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 Ala745Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000116137 SCV000821957 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000194594 SCV000246813 uncertain significance not specified 2015-04-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586157 SCV000699685 uncertain significance not provided 2017-08-16 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2233G>A (p.Ala745Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the P-loop containing nucleoside triphosphate hydrolase domain and ATP-dependent helicase, C-terminal domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC and control cohorts from the literature at a frequency of 0.0000606 (8/132044 control chromosomes), which is approximately equivalent to the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). In the literature, the variant has been identified in breast and ovarian cancer patients without evidence for or against pathogenicity (Ramus_2015, Catucci_2012, Maxwell_2016) . However, an internal LCA sample carries this variant along with a pathogenic BRCA2 mutation (c.5946delT), suggesting the variant is not the cause of disease in this patient. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000477497 SCV000547231 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 745 of the BRIP1 protein (p.Ala745Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587780235, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer and ovarian cancer (PMID: 22692731, 26315354). ClinVar contains an entry for this variant (Variation ID: 128169). 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: "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.
Vantari Genetics RCV000116137 SCV000267030 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-14 criteria provided, single submitter clinical testing

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