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
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.
Ambry Genetics RCV000116137 SCV000186759 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Genetic Services Laboratory, University of Chicago RCV000194594 SCV000246813 uncertain significance not specified 2015-04-11 criteria provided, single submitter clinical testing
Vantari Genetics RCV000116137 SCV000267030 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-14 criteria provided, single submitter clinical testing
Color RCV000116137 SCV000537547 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Invitae RCV000477497 SCV000547231 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-23 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 observed 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.
Integrated Genetics/Laboratory Corporation of America RCV000194594 SCV000699685 uncertain significance not specified 2019-04-22 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2233G>A (p.Ala745Thr) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 261914 control chromosomes. The observed variant frequency is approximately 1.28 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. c.2233G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Ramus_2015, Maxwell_2016, Easton_2016, Catucci_2012, Weber-Lassalle_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5946delT, p.Ser1982fsX22), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS possibly benign variant.
Counsyl RCV000662754 SCV000785542 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-09-06 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116137 SCV000821957 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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