rs138213197

Positions:

chr17-48728343-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4

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 Likely pathogenic,association (★★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

HOXB13
NM_006361.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic; association criteria provided, multiple submitters, no conflicts P:26U:2O:1

Conservation

PhyloP100: 7.40

Variant links:

Genes affected

HOXB13 (HGNC:5112): (homeobox B13) This gene encodes a transcription factor that belongs to the homeobox gene family. Genes of this family are highly conserved among vertebrates and essential for vertebrate embryonic development. This gene has been implicated to play a role in fetal skin development and cutaneous regeneration. In mice, a similar gene was shown to exhibit temporal and spatial colinearity in the main body axis of the embryo, but was not expressed in the secondary axes, which suggests functions in body patterning along the axis. This gene and other HOXB genes form a gene cluster at chromosome the 17q21-22 region. [provided by RefSeq, Jul 2008]

HOXB13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a chain Homeobox protein Hox-B13 (size 283) in uniprot entity HXB13_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_006361.6

PP5

Variant 17-48728343-C-T is Pathogenic according to our data. Variant chr17-48728343-C-T is described in ClinVar as [Likely_pathogenic, association]. Clinvar id is 128031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-48728343-C-T is described in Lovd as [Pathogenic]. Variant chr17-48728343-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.04995072). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOXB13	NM_006361.6 linkuse as main transcript	c.251G>A	p.Gly84Glu	missense_variant	1/2	ENST00000290295.8	NP_006352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOXB13	ENST00000290295.8 linkuse as main transcript	c.251G>A	p.Gly84Glu	missense_variant	1/2	1	NM_006361.6	ENSP00000290295	P1

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00199

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00184

AC:

460

AN:

249538

Hom.:

AF XY:

0.00192

AC XY:

260

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.000386

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00782

Gnomad NFE exome

AF:

0.00241

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00176

AC:

2573

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1271

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00795

Gnomad4 NFE exome

AF:

0.00184

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152272

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.00199

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00158

Hom.:

Bravo

AF:

0.000994

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00215

AC:

261

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00172

ClinVar

Significance: Pathogenic/Likely pathogenic; association

Submissions summary: Pathogenic:26Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11Other:1

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 04, 2022	PP1_strong, PS4 -
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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	HOXB13: PP1:Strong, PS4 -
association, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Prostate cancer, hereditary, 9

Pathogenic:7Uncertain:1

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. -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 25, 2021	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 26, 2022	PS4, PP1_Strong, PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 23, 2018	- -
Uncertain significance, flagged submission	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Jun 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -

HOXB13-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 13, 2024	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. -
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. -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	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 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. -

Familial prostate cancer

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.050

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.45

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.91

MVP

0.90

MPC

1.4

ClinPred

0.11

GERP RS

4.7

Varity_R

0.85

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over