VCV000127939.61 - ClinVar

NM_004655.4(AXIN2):c.1985T>C (p.Leu662Pro)

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.

(17)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(4); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004655.4(AXIN2):c.1985T>C (p.Leu662Pro)

Variation ID: 127939 Accession: VCV000127939.61

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q24.1 17: 65536476 (GRCh38) [ NCBI UCSC ] 17: 63532594 (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	Dec 6, 2016	Oct 20, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004655.4:c.1985T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004646.3:p.Leu662Pro	missense
NM_001363813.1:c.1790T>C	NP_001350742.1:p.Leu597Pro	missense
NC_000017.11:g.65536476A>G
NC_000017.10:g.63532594A>G
NG_012142.1:g.30147T>C
LRG_296:g.30147T>C
LRG_296t1:c.1985T>C

... more HGVS ... less HGVS

Protein change

L662P, L597P

Other names

p.L662P:CTG>CCG

Canonical SPDI

NC_000017.11:65536475:A:G

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.

0.00100 (G)

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

The Genome Aggregation Database (gnomAD) 0.00084

1000 Genomes Project 0.00100

The Genome Aggregation Database (gnomAD), exomes 0.00102

Exome Aggregation Consortium (ExAC) 0.00105

Trans-Omics for Precision Medicine (TOPMed) 0.00114

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00139

1000 Genomes Project 30x 0.00078

Links

ClinGen: CA288092 dbSNP: rs142476324 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	3795	3809

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.
not specified	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jul 31, 2024	RCV000115871.30
Oligodontia-cancer predisposition syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000203710.26
Hereditary cancer-predisposing syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Sep 29, 2020	RCV001013914.11
not provided	Conflicting interpretations of pathogenicity (8)	criteria provided, conflicting classifications	Jul 1, 2024	RCV000857875.40
AXIN2-related disorder	Likely benign (1)	no assertion criteria provided	Jun 22, 2020	RCV004529934.2

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.	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.
Benign (Apr 16, 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: SCV002046907.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022
Uncertain significance (Dec 16, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715460.2 First in ClinVar: Jun 15, 2021 Last updated: May 27, 2023	Number of individuals with the variant: 2
Benign (Jun 07, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001737728.1 First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021	Comment: Variant summary: AXIN2 c.1985T>C (p.Leu662Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more) Variant summary: AXIN2 c.1985T>C (p.Leu662Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 245612 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1985T>C in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with a predominant consensus as likely benign (n=3)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Sep 29, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002537130.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009784.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Likely benign (Feb 01, 2024)	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: SCV000262219.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024
Likely benign (Oct 30, 2018)	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: SCV001174556.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551243.7 First in ClinVar: Jul 27, 2022 Last updated: Aug 04, 2024
Likely benign (Jan 19, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149780.14 First in ClinVar: May 17, 2014 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Oligodontia-cancer predisposition syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000405687.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (Sep 18, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004564655.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001151403.21 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: AXIN2: BS1 Number of individuals with the variant: 3
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799804.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971010.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (Jun 22, 2020)	no assertion criteria provided Method: clinical testing	AXIN2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004723452.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001919267.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929856.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

Variant summary: AXIN2 c.1985T>C (p.Leu662Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 245612 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in AXIN2 causing Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1985T>C in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with a predominant consensus as likely benign (n=3)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs142476324 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004655.4(AXIN2):c.1985T>C (p.Leu662Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142476324 ...