VCV001784003.6 - ClinVar

NM_004655.4(AXIN2):c.1993_1994delinsT (p.Gly665fs)

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.

(3)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004655.4(AXIN2):c.1993_1994delinsT (p.Gly665fs)

Variation ID: 1784003 Accession: VCV001784003.6

Type and length

Indel, 2 bp

Location

Cytogenetic: 17q24.1 17: 65536467-65536468 (GRCh38) [ NCBI UCSC ] 17: 63532585-63532586 (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	Nov 29, 2022	Jul 23, 2024	Apr 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004655.4:c.1993_1994delinsT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004646.3:p.Gly665fs	frameshift
NM_001363813.1:c.1798_1799delinsT	NP_001350742.1:p.Gly600fs	frameshift
NC_000017.11:g.65536467_65536468delinsA
NC_000017.10:g.63532585_63532586delinsA
NG_012142.1:g.30155_30156delinsT
LRG_296:g.30155_30156delinsT
LRG_296t1:c.1993_1994delGGinsT	LRG_296p1:p.Gly665Serfs

... more HGVS ... less HGVS

Protein change

G600fs, G665fs

Other names

Canonical SPDI

NC_000017.11:65536466:CC: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.

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

Links

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.
AXIN2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3698	3712

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	Pathogenic (1)	criteria provided, single submitter	Aug 7, 2020	RCV002416940.2
Oligodontia-cancer predisposition syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 24, 2024	RCV003100988.4

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.
Pathogenic (Jun 05, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Oligodontia-cancer predisposition syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003478873.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 15042511‚ 21416598 Comment: This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly665Serfs24) in the AXIN2 gene. … (more) This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly665Serfs24) in the AXIN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AXIN2 are known to be pathogenic (PMID: 15042511, 21416598). This variant has not been reported in the literature in individuals with AXIN2-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 07, 2020)	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: SCV002718593.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.1993_1994delGGinsT pathogenic mutation, located in coding exon 7 of the AXIN2 gene, results from the deletion of two nucleotides and insertion of one nucleotide … (more) The c.1993_1994delGGinsT pathogenic mutation, located in coding exon 7 of the AXIN2 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.G665Sfs*24). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Apr 24, 2024)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Oligodontia-cancer predisposition syndrome Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV005083621.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

Comment:

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly665Serfs*24) in the AXIN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AXIN2 are known to be pathogenic (PMID: 15042511, 21416598). This variant has not been reported in the literature in individuals with AXIN2-related conditions. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1993_1994delGGinsT pathogenic mutation, located in coding exon 7 of the AXIN2 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.G665Sfs*24). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome.	Marvin ML	American journal of medical genetics. Part A	2011	PMID: 21416598
Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.	Lammi L	American journal of human genetics	2004	PMID: 15042511

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004655.4(AXIN2):c.1993_1994delinsT (p.Gly665fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...