VCV000041535.24 - ClinVar

NM_000038.6(APC):c.695G>A (p.Arg232Gln)

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.

(10)

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_000038.6(APC):c.695G>A (p.Arg232Gln)

Variation ID: 41535 Accession: VCV000041535.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q22.2 5: 112792495 (GRCh38) [ NCBI UCSC ] 5: 112128192 (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	Apr 12, 2013	Jun 17, 2024	Feb 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.695G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Arg232Gln	missense
NM_001127510.3:c.695G>A	NP_001120982.1:p.Arg232Gln	missense
NM_001127511.3:c.676-8784G>A		intron variant
NM_001354895.2:c.695G>A	NP_001341824.1:p.Arg232Gln	missense
NM_001354896.2:c.695G>A	NP_001341825.1:p.Arg232Gln	missense
NM_001354897.2:c.725G>A	NP_001341826.1:p.Arg242Gln	missense
NM_001354898.2:c.620G>A	NP_001341827.1:p.Arg207Gln	missense
NM_001354899.2:c.646-8784G>A		intron variant
NM_001354900.2:c.518G>A	NP_001341829.1:p.Arg173Gln	missense
NM_001354901.2:c.518G>A	NP_001341830.1:p.Arg173Gln	missense
NM_001354902.2:c.725G>A	NP_001341831.1:p.Arg242Gln	missense
NM_001354903.2:c.695G>A	NP_001341832.1:p.Arg232Gln	missense
NM_001354904.2:c.620G>A	NP_001341833.1:p.Arg207Gln	missense
NM_001354905.2:c.518G>A	NP_001341834.1:p.Arg173Gln	missense
NM_001354906.2:c.-341G>A		5 prime UTR
NC_000005.10:g.112792495G>A
NC_000005.9:g.112128192G>A
NG_008481.4:g.104975G>A
LRG_130:g.104975G>A

... more HGVS ... less HGVS

Protein change

R232Q, R207Q, R242Q, R173Q

Other names

Canonical SPDI

NC_000005.10:112792494: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.

0.00020 (A)

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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA012709 dbSNP: rs201727026 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.
APC		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	14981	15119

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 provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Oct 20, 2022	RCV000034420.3
Familial adenomatous polyposis 1	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Feb 22, 2024	RCV000472572.9
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 18, 2023	RCV000490876.11
Classic or attenuated familial adenomatous polyposis	Uncertain significance (1)	criteria provided, single submitter	Jul 22, 2023	RCV003996166.2

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.
Uncertain significance (Sep 13, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000293728.10 First in ClinVar: Jul 24, 2016 Last updated: Apr 17, 2019	Comment: This variant is denoted APC c.695G>A at the cDNA level, p.Arg232Gln (R232Q) at the protein level, and results in the change of an Arginine to … (more) This variant is denoted APC c.695G>A at the cDNA level, p.Arg232Gln (R232Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was observed in 1/570 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Arg232Gln was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg232Gln occurs at a position that is conserved across species and is located in the coiled coil region (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Arg232Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
Uncertain significance (Oct 20, 2022)	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: SCV004220494.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 22703879‚ 32720237 Comment: The frequency of this variant in the general population, 0.000008 (2/251206 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.000008 (2/251206 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMID: 3272037 (2021)) and cancer susceptibility (PMID: 22703879 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Jan 03, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000552660.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 232 of the APC protein (p.Arg232Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 232 of the APC protein (p.Arg232Gln). This variant is present in population databases (rs201727026, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 41535). 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 APC protein function with a negative predictive value of 95%. 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)
Uncertain significance (Aug 05, 2022)	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: SCV000579878.6 First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024	Comment: The p.R232Q variant (also known as c.695G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide … (more) The p.R232Q variant (also known as c.695G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide position 695. The arginine at codon 232 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202903.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Aug 22, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785496.2 First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017	Publications: PubMed (1) PubMed: 22703879
Uncertain significance (Feb 22, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018815.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Jan 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000681839.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 22703879 Comment: This missense variant replaces arginine with glutamine at codon 232 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with glutamine at codon 232 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature, but has been observed in individuals ascertained for non-cancer phenotypes (PMID: 22703879). This variant has been identified in 2/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Jul 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic or attenuated familial adenomatous polyposis (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004837308.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (1) PubMed: 22703879 Comment: This missense variant replaces arginine with glutamine at codon 232 of the APC protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces arginine with glutamine at codon 232 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature, but has been observed in individuals ascertained for non-cancer phenotypes (PMID: 22703879). This variant has been identified in 2/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 5
variant of unknown significance (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043107.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Uncertain significance. Number of individuals with the variant: 1 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)

Comment:

This variant is denoted APC c.695G>A at the cDNA level, p.Arg232Gln (R232Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was observed in 1/570 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Arg232Gln was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg232Gln occurs at a position that is conserved across species and is located in the coiled coil region (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Arg232Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Comment:

The frequency of this variant in the general population, 0.000008 (2/251206 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMID: 3272037 (2021)) and cancer susceptibility (PMID: 22703879 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 232 of the APC protein (p.Arg232Gln). This variant is present in population databases (rs201727026, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 41535). 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 APC protein function with a negative predictive value of 95%. 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.

Comment:

The p.R232Q variant (also known as c.695G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide position 695. The arginine at codon 232 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces arginine with glutamine at codon 232 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature, but has been observed in individuals ascertained for non-cancer phenotypes (PMID: 22703879). This variant has been identified in 2/251206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

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
Racial and Ethnic Disparities in Genetic Testing at a Hereditary Breast and Ovarian Cancer Center.	Chapman-Davis E	Journal of general internal medicine	2021	PMID: 32720237
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879

Text-mined citations for rs201727026 ...

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_000038.6(APC):c.695G>A (p.Arg232Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201727026 ...