ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.778A>G (p.Thr260Ala) (rs138743097)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123365 SCV000166688 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 260 of the BRIP1 protein (p.Thr260Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs138743097, ExAC 0.03%). This variant has been reported in individuals affected with breast and colorectal cancer (PMID: 26976419, 28135145) and in unaffected individuals (PMID: 26315354, 26921362, 28076423). ClinVar contains an entry for this variant (Variation ID: 136154). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on BRIP1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000586716 SCV000210869 uncertain significance not provided 2018-07-17 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.778A>G at the cDNA level, p.Thr260Ala (T260A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). BRIP1 Thr260Ala has been observed in individuals with breast cancer, but has also been observed in healthy controls (Ramus 2015, Easton 2016, Tung 2016, Pritchard 2018). This variant was also observed in at least one individual with colorectal cancer (Yurgelun 2017), and was shown to not segregate with disease in a familial breast cancer kindred (Kim 2017). BRIP1 Thr260Ala 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Thr260Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160362 SCV000215637 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000586716 SCV000699734 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing Variant summary: This c.778A>G variant affects a conserved nucleotide, resulting in amino acid change from Thr to Ala. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 6/121390 control chromosomes at a frequency of 0.0000494, predominantly observed in African subpopulation of ExAC with MAF of 0.0002883. This frequency in African cohort exceeds the maximal expected frequency of a pathogenic allele (0.0000625) in this gene, indicating this variant is possibly a benign rare polymorphism especially in Africans. Multiple clinical labs (via ClinVar) classified this variant as VUS. The variant of interest has not been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Based on the currently available information, this variant has been classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Color RCV000160362 SCV000911045 likely benign Hereditary cancer-predisposing syndrome 2016-03-02 criteria provided, single submitter clinical testing

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