ClinVar Miner

Submissions for variant NM_006361.5(HOXB13):c.251G>A (p.Gly84Glu) (rs138213197)

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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 RCV000561749 SCV000664774 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Significant disease association in appropriately sized case-control study(ies),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000229815 SCV000892224 likely pathogenic not provided 2018-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000229815 SCV000149878 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted HOXB13 c.251G>A at the cDNA level, p.Gly84Glu (G84E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has been studied in many case-control studies examining prostate cancer risk. Most significantly, large prostate cancer case-control meta-analyses focused on this variant have reported overall odds ratios of 3.248 (95% CI: 2.313-4.560, p<0.001), 4.07 (95% CI: 3.05-5.45, p<0.00001), and 4.51 (95% CI: 3.28-6.20, p<0.00001) for prostate cancer (Shang 2013, Huang 2014, Cai 2015). In subset analyses of the Huang et al. (2014) study, higher odds ratios were observed for early-onset, familial, and more aggressive prostate cancer as compared with late onset, sporadic, and less aggressive disease, respectively. This variant has also been reported to segregate with prostate cancer in multiple families (Ewing 2012, Johnson 2014). HOXB13 Gly84Glu was observed at an allele frequency of 0.76% (195/25,746) in individuals of Finnish ancestry in large population cohorts (Lek 2016). This variant is located within the MEIS Interaction Domain I (Williams 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000229815 SCV000289513 risk factor not provided 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 84 of the HOXB13 protein (p.Gly84Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs138213197, ExAC 0.8%). Both population studies and haplotype analyses suggest that this variant is a European founder mutation, explaining the higher frequency in these populations (PMID: 22841674, 23064873). Numerous family studies, population-based case-control studies, and large meta-analyses have shown that this variant confers an elevated risk for prostate cancer (PMID: 23064873, 22841674, 26517352, 23518396, 24026887). In a large meta-analysis involving 11 studies with ~120,000 cases and controls (PMID: 24026887), men carrying this variant had a 4.51-fold higher relative risk of prostate cancer compared with non-carriers (95 % CI 3.28-6.20). Higher risks were observed in individuals with early-onset disease (OR=9.73, 95% CI 6.57-14.39), more than two affected relatives (OR=7.27, 95 % CI 4.02-13.15), and highly aggressive disease (OR=5.81, 95% CI 3.72-9.08). ClinVar contains an entry for this variant (Variation ID: 128031). In summary, this is a frequently observed variant that is associated with an approximate 3- to 4.5-fold increased risk of prostate cancer in European and European-descent populations.
OMIM RCV000714291 SCV000844980 pathogenic Prostate cancer, hereditary, 9 2018-10-23 no assertion criteria provided literature only
University of Washington Department of Laboratory Medicine,University of Washington RCV000210093 SCV000266072 pathogenic Prostate cancer susceptibility 2015-11-20 criteria provided, single submitter clinical testing

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