VCV000822995.16 - ClinVar

NM_006361.6(HOXB13):c.314C>T (p.Thr105Ile)

Germline

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.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006361.6(HOXB13):c.314C>T (p.Thr105Ile)

Variation ID: 822995 Accession: VCV000822995.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.32 17: 48728280 (GRCh38) [ NCBI UCSC ] 17: 46805642 (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 16, 2020	May 1, 2024	Jan 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006361.6:c.314C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006352.2:p.Thr105Ile	missense
NC_000017.11:g.48728280G>A
NC_000017.10:g.46805642G>A
NG_033789.1:g.5470C>T
LRG_771:g.5470C>T
LRG_771t1:c.314C>T

... more HGVS ... less HGVS

Protein change

T105I

Other names

Canonical SPDI

NC_000017.11:48728279:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

0.00040 (A)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

The Genome Aggregation Database (gnomAD) 0.00006

Exome Aggregation Consortium (ExAC) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00010

Links

dbSNP: rs140492479 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	1702	1716

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 29, 2023	RCV001018814.5
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 18, 2024	RCV001065112.12

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.	More information 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.
Uncertain significance (Aug 29, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001180093.5 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 22841674‚ 23064873‚ 28272408 Comment: The p.T105I variant (also known as c.314C>T), located in coding exon 1 of the HOXB13 gene, results from a C to T substitution at nucleotide … (more) The p.T105I variant (also known as c.314C>T), located in coding exon 1 of the HOXB13 gene, results from a C to T substitution at nucleotide position 314. The threonine at codon 105 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Dec 31, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004219915.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (3) PubMed: 28272408‚ 23064873‚ 32040869 Comment: In the published literature, this variant has been reported in individuals with breast cancer (PMID: 32040869 (2020)) and prostate cancer (PMID: 23064873 (2013)). The frequency … (more) In the published literature, this variant has been reported in individuals with breast cancer (PMID: 32040869 (2020)) and prostate cancer (PMID: 23064873 (2013)). The frequency of this variant in the general population, 0.00032 (8/24746 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Oct 26, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001784988.5 First in ClinVar: Aug 14, 2021 Last updated: Nov 25, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of prostate or … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of prostate or breast cancer (PMID: 23064873, 32040869, 22841674); This variant is associated with the following publications: (PMID: 28272408, 23064873, 22841674, 32040869) (less)
Uncertain significance (Jan 18, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001230051.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 23064873‚ 32040869 Comment: This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 105 of the HOXB13 protein (p.Thr105Ile). … (more) This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 105 of the HOXB13 protein (p.Thr105Ile). This variant is present in population databases (rs140492479, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 23064873, 32040869). ClinVar contains an entry for this variant (Variation ID: 822995). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

The p.T105I variant (also known as c.314C>T), located in coding exon 1 of the HOXB13 gene, results from a C to T substitution at nucleotide position 314. The threonine at codon 105 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

In the published literature, this variant has been reported in individuals with breast cancer (PMID: 32040869 (2020)) and prostate cancer (PMID: 23064873 (2013)). The frequency of this variant in the general population, 0.00032 (8/24746 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of prostate or breast cancer (PMID: 23064873, 32040869, 22841674); This variant is associated with the following publications: (PMID: 28272408, 23064873, 22841674, 32040869)

Comment:

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 105 of the HOXB13 protein (p.Thr105Ile). This variant is present in population databases (rs140492479, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 23064873, 32040869). ClinVar contains an entry for this variant (Variation ID: 822995). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation HOXB13 c.853delT in Martinican prostate cancer patients.	Marlin R	The Prostate	2020	PMID: 32040869
Computational Modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer.	Chandrasekaran G	Scientific reports	2017	PMID: 28272408
A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk.	Karlsson R	European urology	2014	PMID: 22841674
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

Text-mined citations for rs140492479 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_006361.6(HOXB13):c.314C>T (p.Thr105Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140492479 ...