rs138213197
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_006361.6(HOXB13):c.251G>A(p.Gly84Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,966 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars). Synonymous variant affecting the same amino acid position (i.e. G84G) has been classified as Likely benign.
Frequency
Consequence
NM_006361.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HOXB13 | NM_006361.6 | c.251G>A | p.Gly84Glu | missense_variant | 1/2 | ENST00000290295.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HOXB13 | ENST00000290295.8 | c.251G>A | p.Gly84Glu | missense_variant | 1/2 | 1 | NM_006361.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00148 AC: 225AN: 152154Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00184 AC: 460AN: 249538Hom.: 2 AF XY: 0.00192 AC XY: 260AN XY: 135390
GnomAD4 exome AF: 0.00176 AC: 2573AN: 1461694Hom.: 4 Cov.: 33 AF XY: 0.00175 AC XY: 1271AN XY: 727162
GnomAD4 genome ? AF: 0.00148 AC: 225AN: 152272Hom.: 1 Cov.: 32 AF XY: 0.00165 AC XY: 123AN XY: 74468
ClinVar
Submissions by phenotype
not provided Pathogenic:11Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2020 | Case control studies report that this variant is associated with prostate cancer with odds ratios ranging from 3.25 to 4.51 (Shang 2013, Huang 2014, Karlsson 2014, Cai 2015, Nyberg 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23099437, 23541221, 26517352, 26108461, 22853031, 24310616, 26638190, 27424772, 27625331, 30665703, 28265568, 25595936, 24148311, 23393222, 23292082, 22841674, 23475555, 23064873, 22781434, 23104005, 25629170, 22714738, 26289772, 26779768, 27004541, 23457453, 27034017, 26604137, 24722062, 23129385, 23396964, 27294245, 26931741, 26671023, 26803986, 25111073, 24026887, 23518396, 22236224, 27153395, 27902461, 27819754, 28050579, 28798948, 28790484, 28657667, 29181843, 28272408, 28186998, 29259341, 29236593, 28598379, 28442163, 30527799, 31137568, 30560549, 31556563, 30777372, 31980526, 32546843, 31948886, 27626483, 31589614, 33504652, 32830201) - |
association, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 84 of the HOXB13 protein (p.Gly84Glu). This variant is present in population databases (rs138213197, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. 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). 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). ClinVar contains an entry for this variant (Variation ID: 128031). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HOXB13 protein function with a negative predictive value of 80%. In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele. - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 04, 2022 | PP1_strong, PS4 - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | HOXB13: PP1:Strong, PS4 - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 25, 2021 | In the published literature, this variant is reported to be significantly associated with an increased risk of prostate cancer, with higher risks observed for early-onset and familial disease compared with late-onset and sporadic disease (PMIDs: 23518396 (2013), 24026887 (2014), and 26517352 (2015)). In addition, this variant is reported to be a founder variant in European populations (PMIDs: 23064873 (2013) and 22841674 (2014)). Furthermore, this variant’s cumulative effects on HOXB13 protein function are inconclusive and require further investigation (PMID: 30560549 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Based on the available information, this variant is classified as pathogenic. - |
Prostate cancer, hereditary, 9 Pathogenic:7Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 23, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Sep 26, 2022 | PS4, PP1_Strong, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 25, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 25, 2019 | The HOXB13 c.251G>A (p.Gly84Glu) variant is a missense variant that has been associated with an increased risk of prostate cancer. Ewing et al. (2012) first identified the p.Gly84Glu variant in a heterozygous state in 18 men from four families with familial prostate cancer. Subsequent large case-control studies and two meta-analysis studies demonstrated that the p.Gly84Glu variant was associated with a significantly increased prostate cancer susceptibility in variant carriers compared with non-carriers, with odds ratios ranging from 3.38-4.51, and was also significantly associated with early-onset, positive family history, and highly aggressive disease (Huang et al. 2014; Zhang et al. 2016). Carriers of the p.Gly84Glu variant were estimated to have a 33-60% lifetime risk of prostate cancer compared to the general population risk of 12% (Karlsson et al. 2014; Hoffman et al. 2015). The p.Gly84Glu variant is reported at a frequency of 0.007618 in the European (Finnish) population of the Genome Aggregation Database and has been identified as a founder variant in European ancestry (Xu et al. 2013). Based on the collective evidence and application of ACMG criteria, the p.Gly84Glu variant is classified as pathogenic for prostate cancer susceptibility. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Jun 24, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 13, 2023 | The p.G84E variant (also known as c.251G>A), located in coding exon 1 of the HOXB13 gene, results from a G to A substitution at nucleotide position 251. The glycine at codon 84 is replaced by glutamic acid, an amino acid with similar properties. This alteration is located in a highly conserved region of HOXB13 that plays an important role in mediating the binding of HOX13 paralogues to the MEIS family of HOX cofactor proteins (Ewing CM et al. N. Engl. J. Med. 2012 Jan;366:141-9). Several large case-control studies have shown an association of the p.G84E alteration with increased prostate cancer risk (Ewing CM et al. N. Engl. J. Med. 2012 Jan;366:141-9; Breyer JP et al. Cancer Epidemiol. Biomarkers Prev. 2012 Aug;21:1348-53; Akbari MR et al. J. Natl. Cancer Inst. 2012 Aug;104:1260-2; Xu J et al. Hum. Genet. 2013 Jan;132:5-14; Karlsson R et al. Eur. Urol. 2014 Jan;65:169-76; Hoffmann TJ et al. PLoS Genet. 2015 Jan;11:e1004930; Karyadi DM et al. Oncotarget. 2017 Jan;8:1495-1507). Meta-analyses have estimated that male carriers of the p.G84E alteration have an approximate 2.8 to 4-fold risk of prostate cancer compared to the general population; however, exact lifetime risk figures are not currently available (Shang Z et al. Eur. Urol. 2013 Jul;64:173-6; Huang H et al. Tumour Biol. 2014 Feb;35:1177-82; Cai Q et al. Oncotarget. 2015 Dec;6:42312-21; Nyberg T et al. Eur. Urol. 2019 05;75(5):834-845). Of note, this alteration has been reported predominantly in individuals of European descent, and is estimated to contribute to up to 5% of high-risk prostate cancer families in this population (Xu J et al. Hum. Genet. 2013 Jan;132:5-14). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Prostate cancer susceptibility Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Breast and/or ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 26, 2023 | - - |
Carcinoma of pancreas Pathogenic:1
Likely pathogenic, no assertion criteria provided | case-control | CZECANCA consortium | Mar 04, 2021 | - - |
HOXB13-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously associated with increased risk for prostate cancer, breast cancer, colorectal cancer, bladder cancer, and leukemia (PMID: 22236224, 22853031, 23541221, 26108461, 26108461). Large prostate cancer case-control meta-analysis studies of this variant have reported odds ratios of 3.25-4.51 for prostate cancer (PMID: 22841674, 23518396, 24026887). Higher odds ratios were observed for early-onset, familial, and highly aggressive prostate cancer (PMID: 24026887). This variant has been reported to segregate with prostate cancer in multiple families (PMID: 22236224). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.19% (528/280842) across all populations and at a frequency of 0.76% (191/25072) in the European Finnish population, suggesting that this variant is a founder mutation in this population. The c.251G>A (p.Gly84Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.251G>A (p.Gly84Glu) variant is classified as Pathogenic. - |
Familial prostate carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2021 | Variant summary: HOXB13 c.251G>A (p.Gly84Glu) 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 0.0018 in 249538 control chromosomes in the gnomAD database, including 2 homozygotes. c.251G>A has been reported in the literature in multiple individuals affected with Prostate Cancer, which include segregation in multiple families, and several studies have reported the variant as a European founder mutation. Family studies, population-based case-control studies, and large meta-analyses have shown the variant to confer an elevated risk for prostate cancer (eg. Huang_2014, Cai_2015, Ewing_2012). For example, a meta-analyses of 11 studies including 120,167 participants reported that men with the HOXB13 G84E variant had a 4.51-fold higher relative risk of prostate cancer compared with non-carriers (95 % CI 3.28-6.20; Huang_2014). The much higher risks were observed in individuals with early onset (odds ratio (OR)=9.73, 95 % confidence interval 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). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
HOXB13-Related Cancer Predisposition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously associated with increased risk for prostate cancer, colorectal cancer, bladder cancer, and leukemia (PMID: 22236224, 23541221, 26108461). Large prostate cancer case-control meta-analysis studies of this variant have reported odds ratios of 3.25-4.51 for prostate cancer (PMID: 22841674, 23518396, 24026887). Higher odds ratios were observed for early-onset, familial, and highly aggressive prostate cancer (PMID: 24026887). This variant has been reported to segregate with prostate cancer in multiple families (PMID: 22236224). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.19% (528/280842) across all populations and at a frequency of 0.76% (191/25072) in the European Finnish population, suggesting that this variant is a founder mutation in this population. The c.251G>A (p.Gly84Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.251G>A (p.Gly84Glu) variant is classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at