VCV000128031.100 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic; association
Pathogenic (16); Likely pathogenic (10)

27 out of 37 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 128031 Accession: VCV000128031.100

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.32 17: 48728343 (GRCh38) [ NCBI UCSC ] 17: 46805705 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 20, 2016	Jul 27, 2026	Feb 3, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_006361.6:c.251G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006352.2:p.Gly84Glu	missense
NC_000017.11:g.48728343C>T
NC_000017.10:g.46805705C>T
NG_033789.1:g.5407G>A
LRG_771:g.5407G>A
LRG_771t1:c.251G>A	LRG_771p1:p.Gly84Glu
	Q92826:p.Gly84Glu

... more HGVS ... less HGVS

Protein change

G84E

Other names

p.G84E:GGA>GAA

Canonical SPDI

NC_000017.11:48728342:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00099

The Genome Aggregation Database (gnomAD) 0.00150

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00154

The Genome Aggregation Database (gnomAD) 0.00160

The Genome Aggregation Database (gnomAD), exomes 0.00177

The Genome Aggregation Database (gnomAD), exomes 0.00184

Exome Aggregation Consortium (ExAC) 0.00218

Links

ClinGen: CA288225 Genetic Testing Registry (GTR): GTR000558853 UniProtKB: Q92826#VAR_071866 OMIM: 604607.0001 dbSNP: rs138213197 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HOXB13		-	-	GRCh38 GRCh37	1936	1950

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Prostate cancer susceptibility	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 18, 2025	RCV000210093.7
not provided	Pathogenic/Likely pathogenic; association (13)	criteria provided, multiple submitters, no conflicts	Feb 3, 2026	RCV000229815.72
Hereditary cancer-predisposing syndrome	Likely pathogenic (2)	criteria provided, single submitter	Oct 17, 2025	RCV000561749.14
Prostate cancer, hereditary, 9	Pathogenic/Likely pathogenic (14)	criteria provided, multiple submitters, no conflicts	Oct 29, 2025	RCV000714291.28
Carcinoma of pancreas	Likely pathogenic (1)	no assertion criteria provided	Mar 4, 2021	RCV001391199.4
Familial prostate cancer	Pathogenic (1)	criteria provided, single submitter	Aug 23, 2021	RCV001582580.5
HOXB13-Related Cancer Predisposition	Pathogenic (1)	criteria provided, single submitter	Mar 29, 2024	RCV003335105.2
Breast and/or ovarian cancer	Likely pathogenic (1)	criteria provided, single submitter	Apr 26, 2023	RCV003492500.1
HOXB13-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV004549575.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 23, 2021) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Familial prostate cancer	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001821360.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Publications: PubMed (3) PubMed: 22236224‚ 24026887‚ 26517352 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 25, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000149878.13 First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019	Comment: show 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) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 04, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Prostate cancer, hereditary, 9	Mendelics Accession: SCV002516559.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 26, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: HudsonAlpha-COAGS Accession: SCV002575021.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022	Comment: show PS4, PP1_Strong, PP3 (less) Observation: 1 Collection method: research Allele origin: unknown Affected status: unknown more Observation 1 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1

Likely pathogenic (Nov 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009557.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided

Likely pathogenic (Apr 26, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Breast and/or ovarian cancer	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004240700.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Mar 25, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	Baylor Genetics Accession: SCV004199911.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely Pathogenic (Oct 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Prostate cancer, hereditary, 9	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV005877692.1 First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025	Comment: show 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 â€“ 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Aug 09, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	MGZ Medical Genetics Center Accession: SCV002580137.2 First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025 Comment: ACMG criteria applied: PS4, PP1, PP3, BS2	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 13 Sex: female

Pathogenic (Sep 21, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV006054278.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Publications: PubMed (6) PubMed: 22236224‚ 23064873‚ 23396964‚ 25629170‚ 26108461‚ 26779768 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Nov 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer susceptibility	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV007107091.1 First in ClinVar: May 23, 2026 Last updated: May 23, 2026	Publications: PubMed (5) PubMed: 22841674‚ 23064873‚ 23518396‚ 24026887‚ 26517352 Comment: show Case-control data demonstrate that the c.251G>A (p.Gly84Glu) variant is strongly associated with an increased risk of early-onset prostate cancer. The following ACMG criteria has been used: PS4; PP1_Strong (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Sex: male

pathogenic (Aug 11, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002774349.3 First in ClinVar: Dec 31, 2022 Last updated: Dec 07, 2025	Publications: PubMed (12) PubMed: 22236224‚ 22781434‚ 22841674‚ 23064873‚ 23292082‚ 23518396‚ 24026887‚ 26517352‚ 27902461‚ 30527799‚ 30560549‚ 32546843 Comment: show The HOXB13 c.251G>A (p.Gly84Glu) variant has been reported in the published literature 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 (PMID: 22781434 (2012), 22236224 (2012), 23292082 (2013), 23064873 (2013), 23518396 (2013), 22841674 (2014), 24026887 (2014), 26517352 (2015), 27902461 (2017), 30527799 (2019)), and has been observed in individuals with breast cancer (PMID: 23292082 (2013), 26517352 (2015), 32546843 (2020)), and colorectal cancer (PMID: 23292082 (2013), 26517352 (2015). In addition, this variant is reported to be a founder variant in European populations (PMIDs: 23064873 (2013) and 22841674 (2014)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Oct 17, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000664774.7 First in ClinVar: Jan 01, 2018 Last updated: Jan 11, 2026	Publications: PubMed (21) PubMed: 15964834‚ 17138648‚ 22236224‚ 22714738‚ 22781434‚ 22841674‚ 22853031‚ 23064873‚ 23292082‚ 23457453‚ 23518396‚ 24026887‚ 25206306‚ 25629170‚ 26108461‚ 26517352‚ 27153395‚ 27424772‚ 27902461‚ 28798948‚ 8756292 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 25, 2025) C Contributing to aggregate classification	criteria provided, single submitter (DASA Assertion Criteria)	not provided	Dasa Accession: SCV007599523.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Publications: PubMed (11) PubMed: 22236224‚ 22781434‚ 22841674‚ 23457453‚ 23518396‚ 24026887‚ 25629170‚ 26108461‚ 26517352‚ 27626483‚ 30527799 Comment: show NM_006361.6(HOXB13):c.251G>A (p.Gly84Glu) is a missense variant that results in the substitution of glycine with glutamic acid. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 22236224; PMID: 26108461; PMID: 23457453; PMID: 23518396; PMID: 24026887). This variant has been recurrently observed in individuals with related phenotype (PMID: 22236224; PMID: 26108461; PMID: 23457453; PMID: 23518396; PMID: 24026887). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9 (Autosomal dominant inheritance)	CHARM Consortium Accession: SCV007602328.1 First in ClinVar: Jun 14, 2026 Last updated: Jun 14, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) Sex: female Comment on evidence: Observed in 1 individual with germline variant in PALB2 and FANCM

Pathogenic (Nov 20, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Prostate cancer susceptibility	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266072.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Observation: 6 Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Clinical Features: ovarian cancer (present) Age: 60-69 years Observation 2 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 40-49 years Observation 3 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 40-49 years Observation 4 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 40-49 years Observation 5 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Clinical Features: colon cancer (present) Age: 50-59 years Observation 6 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 60-69 years

Pathogenic (Jul 25, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Prostate cancer, hereditary, 9	Illumina Laboratory Services, Illumina Accession: SCV001451564.1 First in ClinVar: Dec 23, 2020 Last updated: Dec 23, 2020	Publications: PubMed (6) PubMed: 22236224‚ 22841674‚ 23064873‚ 24026887‚ 25629170‚ 27626483 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	HOXB13-related disorders	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046272.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (May 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	Fulgent Genetics, Fulgent Genetics Accession: SCV005644237.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004026833.2 First in ClinVar: Aug 19, 2023 Last updated: Mar 11, 2025	Publications: PubMed (10) PubMed: 17138648‚ 22853031‚ 23064873‚ 24026887‚ 26779768‚ 27626483‚ 28050579‚ 30527799‚ 32546843‚ 32830201 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	HOXB13-Related Cancer Predisposition	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046400.2 First in ClinVar: Oct 21, 2023 Last updated: Mar 29, 2025	Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jan 20, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002522530.2 First in ClinVar: Jun 05, 2022 Last updated: Jan 11, 2026	Publications: PubMed (10) PubMed: 22841674‚ 23064873‚ 23457453‚ 23518396‚ 24026887‚ 26517352‚ 27626483‚ 28050579‚ 30527799‚ 30560549 Comment: show PP1_strong, PS4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 3

association (Feb 03, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000289513.11 First in ClinVar: Jul 03, 2016 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 22841674‚ 23064873‚ 23518396‚ 24026887‚ 26517352 Comment: show 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 approximately 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007449058.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 22236224‚ 22781434‚ 22841674‚ 24026887‚ 25595936‚ 26517352 Comment: show This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:26517352, 24026887, 25595936, 22841674, 22781434). This variant has been shown to segregate with disease in multiple affected family members (ACMG/AMP: PP1_Strong; PMID:22236224). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	Otogenetics Accession: SCV007539665.1 First in ClinVar: Apr 12, 2026 Last updated: Apr 12, 2026	Publications: PubMed (6) PubMed: 22236224‚ 22714738‚ 26517352‚ 27626483‚ 32830201‚ 33099213 Comment: show PS4: Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls: three case-control studies investigating the p.G84E mutation indicate a prostate cancer OR between 3.25 and 4.81, with valid confidence intervals and p-values < 0.001 (PMID: 26517352, 27626483, 32830201); PM2: Maximum gnomAD MAF of 0.762% in European-Finnish (FIN) subpopulation (<1.0% threshold); PP1_Strong: Cosegregation with prostate cancer across multiple affected family members (PMID: 22236224, 22714738, 33099213) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 25, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Prostate cancer, hereditary, 9	Genetics and Molecular Pathology, SA Pathology Accession: SCV002556661.3 First in ClinVar: Aug 04, 2022 Last updated: Jul 14, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Nov 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV000892224.41 First in ClinVar: Mar 31, 2019 Last updated: Jul 27, 2026	Comment: show HOXB13: PP1:Strong, PS4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 20

Pathogenic (Oct 23, 2018) N Not contributing to aggregate classification	no assertion criteria provided	PROSTATE CANCER, HEREDITARY, 9	OMIM Accession: SCV000844980.1 First in ClinVar: Oct 29, 2018 Last updated: Oct 29, 2018	Publications: PubMed (1) PubMed: 22236224 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2018. Baltimore, Md. Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: To identify a prostate cancer susceptibility gene in the 17q21-q22 region (HPC9; 610997), Ewing et al. (2012) sequenced 2,009 exons from 202 genes in germline … (more) To identify a prostate cancer susceptibility gene in the 17q21-q22 region (HPC9; 610997), Ewing et al. (2012) sequenced 2,009 exons from 202 genes in germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. They then tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from 4 families were discovered to have a rare but recurrent mutation, G84E (rs138213197), in HOXB13. All 18 men with prostate cancer and available DNA in these 4 families carried the mutation. At the time of the analysis the G84E mutation was not reported in dbSNP or in the NCBI 1000 Genomes sequencing project (May 2011), which included 1,094 subjects, 381 of European descent. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5,083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1,401 control subjects (0.1%) (P = 8.5 x 10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0 x 10(-6)). Hamosh (2018) noted that the G84E mutation in the HOXB13 gene was present in 530 of 275,718 alleles and in 2 homozygotes in the gnomAD database (October 23, 2018). (less)

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV001974877.2 First in ClinVar: Oct 07, 2021 Last updated: Oct 16, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jun 13, 2024) N Not contributing to aggregate classification	no assertion criteria provided	HOXB13-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005356427.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Mar 04, 2021) N Not contributing to aggregate classification	no assertion criteria provided	Carcinoma of pancreas	CZECANCA consortium Accession: SCV001593142.1 First in ClinVar: May 14, 2021 Last updated: May 14, 2021	Observation: 1 Collection method: case-control Allele origin: germline Affected status: yes more Observation 1 Collection method: case-control Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799539.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808755.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743393.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001957343.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Jun 24, 2021) N Not contributing to aggregate classification	Flagged submission flagged submission Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Prostate cancer, hereditary, 9	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002011756.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (-) N Not contributing to aggregate classification	Flagged submission flagged submission (ACMG Guidelines, 2015) Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Hereditary cancer-predisposing syndrome	Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf Accession: SCV001482293.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Observation: 1 Collection method: research Allele origin: paternal Affected status: yes more Observation 1 Collection method: research Allele origin: paternal Affected status: yes Test name: Whole-Exome sequencing Zygosity: 1 Single Heterozygote Family history: no Platform type: Next Generation Sequencing

Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

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.

Comment:

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)

Comment:

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 â€“ 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.

Comment:

The HOXB13 c.251G>A (p.Gly84Glu) variant has been reported in the published literature 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 (PMID: 22781434 (2012), 22236224 (2012), 23292082 (2013), 23064873 (2013), 23518396 (2013), 22841674 (2014), 24026887 (2014), 26517352 (2015), 27902461 (2017), 30527799 (2019)), and has been observed in individuals with breast cancer (PMID: 23292082 (2013), 26517352 (2015), 32546843 (2020)), and colorectal cancer (PMID: 23292082 (2013), 26517352 (2015). In addition, this variant is reported to be a founder variant in European populations (PMIDs: 23064873 (2013) and 22841674 (2014)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, this variant is classified as pathogenic.

Comment:

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.

Comment:

NM_006361.6(HOXB13):c.251G>A (p.Gly84Glu) is a missense variant that results in the substitution of glycine with glutamic acid. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 22236224; PMID: 26108461; PMID: 23457453; PMID: 23518396; PMID: 24026887). This variant has been recurrently observed in individuals with related phenotype (PMID: 22236224; PMID: 26108461; PMID: 23457453; PMID: 23518396; PMID: 24026887). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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 approximately 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.

Comment:

This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:26517352, 24026887, 25595936, 22841674, 22781434). This variant has been shown to segregate with disease in multiple affected family members (ACMG/AMP: PP1_Strong; PMID:22236224).

Comment:

PS4: Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls: three case-control studies investigating the p.G84E mutation indicate a prostate cancer OR between 3.25 and 4.81, with valid confidence intervals and p-values < 0.001 (PMID: 26517352, 27626483, 32830201); PM2: Maximum gnomAD MAF of 0.762% in European-Finnish (FIN) subpopulation (<1.0% threshold); PP1_Strong: Cosegregation with prostate cancer across multiple affected family members (PMID: 22236224, 22714738, 33099213)

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The HOXB13 p.Gly84Glu variant observed in an extended five generation high-risk prostate cancer pedigree supports risk association for multiple cancer sites.	Cannon-Albright LA	Cancer epidemiology	2020	PMID: 33099213
Germline HOXB13 G84E mutation carriers and risk to twenty common types of cancer: results from the UK Biobank.	Wei J	British journal of cancer	2020	PMID: 32830201
Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.	Liu J	Scientific reports	2020	PMID: 32546843
HOXB13 interaction with MEIS1 modifies proliferation and gene expression in prostate cancer.	Johng D	The Prostate	2019	PMID: 30560549
Homeobox B13 G84E Mutation and Prostate Cancer Risk.	Nyberg T	European urology	2019	PMID: 30527799
HOXB13 mutations and binding partners in prostate development and cancer: Function, clinical significance, and future directions.	Brechka H	Genes & diseases	2017	PMID: 28798948
Whole exome sequencing in 75 high-risk families with validation and replication in independent case-control studies identifies TANGO2, OR5H14, and CHAD as new prostate cancer susceptibility genes.	Karyadi DM	Oncotarget	2017	PMID: 27902461
Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis.	Cardoso M	Oncoscience	2016	PMID: 28050579
Association between germline homeobox B13 (HOXB13) G84E allele and prostate cancer susceptibility: a meta-analysis and trial sequential analysis.	Zhang J	Oncotarget	2016	PMID: 27626483
Recurrent HOXB13 mutations in the Dutch population do not associate with increased breast cancer risk.	Liu J	Scientific reports	2016	PMID: 27424772
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness.	Storebjerg TM	BJU international	2016	PMID: 26779768
Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates.	Cai Q	Oncotarget	2015	PMID: 26517352
The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies.	Beebe-Dimmer JL	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2015	PMID: 26108461
Imputation of the rare HOXB13 G84E mutation and cancer risk in a large population-based cohort.	Hoffmann TJ	PLoS genetics	2015	PMID: 25629170
Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.	Kote-Jarai Z	Annals of oncology : official journal of the European Society for Medical Oncology	2015	PMID: 25595936
Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer.	Decker B	Pharmacogenomics and personalized medicine	2014	PMID: 25206306
G84E mutation in HOXB13 is firmly associated with prostate cancer risk: a meta-analysis.	Huang H	Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine	2014	PMID: 24026887
A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk.	Karlsson R	European urology	2014	PMID: 22841674
Germline homeobox B13 (HOXB13) G84E mutation and prostate cancer risk in European descendants: a meta-analysis of 24,213 cases and 73, 631 controls.	Shang Z	European urology	2013	PMID: 23518396
Population-based estimate of prostate cancer risk for carriers of the HOXB13 missense mutation G84E.	MacInnis RJ	PloS one	2013	PMID: 23457453
HOXB13 mutation and prostate cancer: studies of siblings and aggressive disease.	Witte JS	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2013	PMID: 23396964
HOXB13 G84E mutation in Finland: population-based analysis of prostate, breast, and colorectal cancer risk.	Laitinen VH	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2013	PMID: 23292082
HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).	Xu J	Human genetics	2013	PMID: 23064873
Association of a HOXB13 variant with breast cancer.	Alanee S	The New England journal of medicine	2012	PMID: 22853031
Association between germline HOXB13 G84E mutation and risk of prostate cancer.	Akbari MR	Journal of the National Cancer Institute	2012	PMID: 22781434
Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer.	Breyer JP	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2012	PMID: 22714738
Germline mutations in HOXB13 and prostate-cancer risk.	Ewing CM	The New England journal of medicine	2012	PMID: 22236224
Posterior Hox gene expression and differential androgen regulation in the developing and adult rat prostate lobes.	Huang L	Endocrinology	2007	PMID: 17138648
Hoxb13 up-regulates transglutaminase activity and drives terminal differentiation in an epidermal organotypic model.	Mack JA	The Journal of biological chemistry	2005	PMID: 15964834
Hoxb-13: a new Hox gene in a distant region of the HOXB cluster maintains colinearity.	Zeltser L	Development (Cambridge, England)	1996	PMID: 8756292
Hamosh, A. Personal Communication. 2018. Baltimore, Md.	-	-	-	-
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Text-mined citations for rs138213197 ...

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Record last updated Jul 27, 2026