ClinVar Miner

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

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Total submissions: 6
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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 2019-08-30 criteria provided, single submitter clinical testing 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 2019-12-17 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 2019-06-21 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.
Illumina Clinical Services Laboratory,Illumina RCV001125838 SCV001284960 uncertain significance Fanconi anemia, complementation group J 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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