ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.550G>T (p.Asp184Tyr) (rs201047375)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132540 SCV000187637 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212302 SCV000210820 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.550G>T at the cDNA level, p.Asp184Tyr (D184Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has been observed in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps and one individual with sarcoma (Yurgelun 2015, Ballinger 2016). Additionally, BRIP1 Asp184Tyr has been observed in males and females with breast cancer, but has also been observed in control populations (Lu 2015, Ramus 2015, Easton 2016, Shirts 2016, Rummel 2017, Fostira 2018). Vel?zquez et al. (2018) reported that this variant results in exon 5 skipping due to creation of a splice enhancer site. BRIP1 Asp184Tyr was observed at an allele frequency of 0.02% (28/126622) in individuals of European 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Asp184Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168177 SCV000218840 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 184 of the BRIP1 protein (p.Asp184Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs201047375, ExAC 0.03%). This variant has been observed in individuals affected with breast cancer and Lynch syndrome-associated cancers, as well as healthy individuals (PMID: 26845104, 28503720, 26921362, 25186627, 30230034, 29368626, 25980754, 29335925). In one of these individuals affected with breast cancer, a pathogenic allele was also identified in BRIP1, which suggests that this c.550G>T variant was not the primary cause of disease. (Invitae). ClinVar contains an entry for this variant (Variant ID: 143021). Experimental studies have shown that this variant results in exon 5 skipping (PMID: 30230034). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000132540 SCV000266160 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000132540 SCV000684286 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing
Counsyl RCV000662870 SCV000785762 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-11-29 criteria provided, single submitter clinical testing
GeneKor MSA RCV000132540 SCV000821966 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000168177 SCV000895116 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212302 SCV001134032 uncertain significance not provided 2019-04-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192824 SCV001361199 uncertain significance not specified 2019-10-21 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.550G>T (p.Asp184Tyr) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Four of five computational tools predict no significant impact on normal splicing. However, a functional study, Velazquez_2019, found the variant to cause exon 5 skipping. The variant allele was found at a frequency of 0.0001 in 251332 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.5-fold over the estimated maximal allele frequency expected for a pathogenic variant in BRIP1 causing Breast Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.550G>T has been reported in the literature in individuals affected with Breast, Prostate, Pancreatic, Colon, and unidentified cancers (Dudley_2018, Easton_2016, Fostira_2018, Lu_2015, Mouradov_2014, Rummel_2017, Shirts_2015, Tsaousis_2019, Tung_2014, Velazquez_2019, Weber-Lassalle_2018, Yurgelun_2015). One family, described in Velazquez_2019, shows the variant does not segregate with disease, therefore, suggesting reduced penetrance. Eight ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. One submission indicates the variant co-occurs with a pathogenic BRIP1 variant (variant not provided). Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196849 SCV001367482 uncertain significance Abnormal macular morphology; Pattern dystrophy of the retina 2020-01-17 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3. This variant was detected in heterozygous state.

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