ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1442G>A (p.Gly481Asp) (rs200062099)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130729 SCV000185619 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000212311 SCV000210844 uncertain significance not provided 2018-07-31 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1442G>A at the cDNA level, p.Gly481Asp (G481D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has been reported in individuals with breast cancer, dermatofibrosarcoma, or familial prostate cancer (Lu 2015, Ballinger 2016, Hayano 2016, Kim 2016, Wong 2016). BRIP1 Gly481Asp was observed at an allele frequency of 0.15% (27/18588) in individuals of East Asian ancestry in large population cohorts (Lek 2016). BRIP1 Gly481Asp 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 Gly481Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130729 SCV000537588 likely benign Hereditary cancer-predisposing syndrome 2020-05-11 criteria provided, single submitter clinical testing
Invitae RCV000469846 SCV000547296 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 481 of the BRIP1 protein (p.Gly481Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs200062099, ExAC 0.2%). This variant has been reported in individuals affected with breast cancer (PMID: 26790966, 26689913, 29263802), pancreatic cancer (PMID: 29667044), and prostate cancer (PMID: 27701467). ClinVar contains an entry for this variant (Variation ID: 141975). 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.
Counsyl RCV000663131 SCV000786268 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2018-04-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780054 SCV000917075 likely benign not specified 2019-05-24 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1442G>A (p.Gly481Asp) results in a non-conservative amino acid change in 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 0.00012 in 243572 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 24 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 a benign polymorphism found primarily in populations of East Asian origin. c.1442G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and pancreatic ductal adenocarcinoma (Lu_2015, Wong_2016, Kim_2016, Hayano_2016, Ohmoto_2018), without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030540 SCV001193536 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV001124864 SCV001283865 uncertain significance Fanconi anemia, complementation group J 2017-06-12 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.
Leiden Open Variation Database RCV000780054 SCV001364523 benign not specified 2019-08-13 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

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