ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.820A>G (p.Thr274Ala) (rs62620988)

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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 RCV000130310 SCV000185160 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000588437 SCV000567806 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.820A>G at the cDNA level, p.Thr274Ala (T274A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has been observed in at least one individual with breast cancer; however, this variant was seen in 8/36,687 control individuals and was absent from 6,341 breast and 706 ovarian cancer cases in a large case/control study (Tung 2016, Weber-Lassalle 2018). BRIP1 Thr274Ala 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Thr274Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000527670 SCV000633716 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 274 of the BRIP1 protein (p.Thr274Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs62620988, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 141694). 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: "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.
Color RCV000130310 SCV000684305 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588437 SCV000699735 likely benign not provided 2016-12-16 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.820A>G (p.Thr274Ala) variant involves the alteration of a conserved nucleotide, is located in ATP-binding domain of the protein, and is predicted to be damaging by 3/4 in silico tools. However in silico prediction results are not definitive and needs be confirmed by functional assays. This variant was found in 8/121382 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0001199 (8/66732). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In literature, this variant has been reported in one breast cancer patient who also carried another pathogenic variant BRCA2 c.7618-1G>A (Tung_2016), supporting for the benign outcome. A clinical lab in ClinVar has classified this variant as uncertain significance without evidence to independently evaluate. Taken together, this variant is classified as Likely Benign.

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