Submissions for variant NM_006361.6(HOXB13):c.251G>A (p.Gly84Glu)

gnomAD frequency: 0.00160  dbSNP: rs138213197

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000229815	SCV000149878	pathogenic	not provided	2020-03-25	criteria provided, single submitter	clinical testing	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)
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229815	SCV000289513	association	not provided	2025-02-03	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000561749	SCV000664774	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-10-17	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000229815	SCV000892224	likely pathogenic	not provided	2025-04-01	criteria provided, single submitter	clinical testing	HOXB13: PP1:Strong, PS4
Illumina Laboratory Services, Illumina	RCV000714291	SCV001451564	pathogenic	Prostate cancer, hereditary, 9	2019-07-25	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582580	SCV001821360	pathogenic	Familial prostate cancer	2021-08-23	criteria provided, single submitter	clinical testing	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000229815	SCV002009557	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000714291	SCV002516559	pathogenic	Prostate cancer, hereditary, 9	2022-05-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000229815	SCV002522530	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	PP1_strong, PS4
Genetics and Molecular Pathology, SA Pathology	RCV000714291	SCV002556661	pathogenic	Prostate cancer, hereditary, 9	2021-11-25	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000714291	SCV002575021	pathogenic	Prostate cancer, hereditary, 9	2022-09-26	criteria provided, single submitter	research	PS4, PP1_Strong, PP3
MGZ Medical Genetics Center	RCV000714291	SCV002580137	likely pathogenic	Prostate cancer, hereditary, 9	2022-08-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000229815	SCV002774349	pathogenic	not provided	2021-06-25	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000229815	SCV004026833	likely pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004549575	SCV004046272	pathogenic	HOXB13-related disorder		criteria provided, single submitter	clinical testing	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335105	SCV004046400	pathogenic	HOXB13-Related Cancer Predisposition	2024-03-29	criteria provided, single submitter	clinical testing	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. This variant that has been previously reported has a heterozygous change in individuals with increased risk for prostate cancer, breast cancer, colorectal cancer, bladder cancer, and leukemia (PMID: 22236224, 22853031, 23541221, 26108461). Large studies comparing prostate cancer cases due to the c.251G>A (p.Gly84Glu) variant versus healthy controls have demonstrated that the variant is strongly associated with an increased risk of early-onset prostate cancer (PMID: 22841674, 23518396, 24026887). Additionally, 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 v4 population database at a frequency of 0.2% (2788/1613966) across all populations and at a frequency of 0.8% (487/63846) in the European Finnish population, suggesting a founder effect. Based on the available evidence, the c.251G>A (p.Gly84Glu) variant is classified as Pathogenic.
Baylor Genetics	RCV000714291	SCV004199911	likely pathogenic	Prostate cancer, hereditary, 9	2024-03-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492500	SCV004240700	likely pathogenic	Breast and/or ovarian cancer	2023-04-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000714291	SCV005644237	likely pathogenic	Prostate cancer, hereditary, 9	2024-05-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000714291	SCV005877692	likely pathogenic	Prostate cancer, hereditary, 9	2024-10-09	criteria provided, single submitter	clinical testing	The HOXB13 c.251G>A; p.Gly84Glu variant (rs138213197, ClinVar Variation ID 128031) is reported in the literature in individuals affected with prostate, breast, and colorectal cancers (selected references: Akbari 2012, Laitinen 2013, Ewing 2012). Large meta-analyses have shown that this variant is associated with an increased risk for prostate cancer (odds ratios: 3.25 – 4.51) and even higher risk for early onset prostate cancer (Cai 2015, Huang 2014, Shang 2013). In the Genome Aggregation Database (v2.1.1), this variant is found primarily in the Finnish and non-Finnish European populations with an allele frequency of 0.76% (191/25072 alleles, including 1 homozygote) and 0.24% (311/ 128106 alleles, including 1 homozygote) respectively. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.448). Base on the available information the p.Gly84Glu variant is considered to be a likely pathogenic risk allele. References: Akbari MR et al. The HOXB13 p.Gly84Glu mutation is not associated with the risk of breast cancer. Breast Cancer Res Treat. 2012 Dec;136(3):907-9. PMID: 23099437. Cai Q et al. Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates. Oncotarget. 2015 Dec 8;6(39):42312-21. PMID: 26517352. Ewing CM et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med. 2012 Jan 12;366(2):141-9. PMID: 22236224. Huang H et al. G84E mutation in HOXB13 is firmly associated with prostate cancer risk: a meta-analysis. Tumour Biol. 2014 Feb;35(2):1177-82. PMID: 24026887. Laitinen VH et al. HOXB13 G84E mutation in Finland: population-based analysis of prostate, breast, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2013 Mar;22(3):452-60. PMID: 23292082. Shang Z et al. Germline homeobox B13 (HOXB13) G84E mutation and prostate cancer risk in European descendants: a meta-analysis of 24,213 cases and 73, 631 controls. Eur Urol. 2013 Jul;64(1):173-6. PMID: 23518396.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000714291	SCV006054278	pathogenic	Prostate cancer, hereditary, 9	2021-09-21	criteria provided, single submitter	clinical testing
OMIM	RCV000714291	SCV000844980	pathogenic	Prostate cancer, hereditary, 9	2018-10-23	no assertion criteria provided	literature only
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	RCV000561749	SCV001482293	uncertain significance	Hereditary cancer-predisposing syndrome		flagged submission	research
CZECANCA consortium	RCV001391199	SCV001593142	likely pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000229815	SCV001743393	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000229815	SCV001799539	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000229815	SCV001808755	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000229815	SCV001957343	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000229815	SCV001974877	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000714291	SCV002011756	uncertain significance	Prostate cancer, hereditary, 9	2021-06-24	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549575	SCV005356427	pathogenic	HOXB13-related disorder	2024-06-13	no assertion criteria provided	clinical testing	The HOXB13 c.251G>A variant is predicted to result in the amino acid substitution p.Gly84Glu. This variant has been reported in many individuals with prostate cancer and has been found to segregate with prostate cancer in several families (Ewing et al. 2012. PubMed ID: 22236224; Breyer et al. 2012. PubMed ID: 22714738; Akbari et al. 2012. PubMed ID: 22781434; Karlsson et al. 2012. PubMed ID: 22841674; Xu et al. 2012. PubMed ID: 23064873). A large meta-analysis of 11 studies found the p.Gly84Glu variant is more frequently found in individuals with prostate cancer in comparison to controls (Huang and Cai. 2014. PubMed ID: 24026887). In addition, this study indicated that men that carry the p.Gly84Glu variant are at a 4.51-fold higher relative risk of prostate cancer in comparison to non-carriers (Huang and Cai. 2014. PubMed ID: 24026887). Additional studies have estimated a 2.8 to 4.5 fold risk of prostate cancer in men in comparison to the general population (Nyberg et al. 2019. PubMed ID: 30527799; Cai et al. 2015. PubMed ID: 26517352). This variant is reported in 0.76% of alleles in individuals of European (Finnish) descent in gnomAD and is reported in two homozygous individuals. Although this variant allele frequency is relatively high, haplotype and population analysis indicate this is a founder variant in European populations (Karlsson et al. 2012. PubMed ID: 22841674; Xu et al. 2012. PubMed ID: 23064873). This variant has conflicting interpretations in ClinVar including pathogenic, likely pathogenic, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128031/). Taken together, we interpret this variant as pathogenic.