VCV000218010.34 - ClinVar

NM_000038.6(APC):c.95A>G (p.Asn32Ser)

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.

(13)

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(6); 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_000038.6(APC):c.95A>G (p.Asn32Ser)

Variation ID: 218010 Accession: VCV000218010.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q22.2 5: 112754985 (GRCh38) [ NCBI UCSC ] 5: 112090682 (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 21, 2015	Sep 16, 2024	Jul 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.95A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Asn32Ser	missense
NM_001127510.3:c.95A>G	NP_001120982.1:p.Asn32Ser	missense
NM_001127511.3:c.166-11341A>G		intron variant
NM_001354895.2:c.95A>G	NP_001341824.1:p.Asn32Ser	missense
NM_001354896.2:c.95A>G	NP_001341825.1:p.Asn32Ser	missense
NM_001354897.2:c.166-11341A>G		intron variant
NM_001354898.2:c.61-11341A>G		intron variant
NM_001354899.2:c.95A>G	NP_001341828.1:p.Asn32Ser	missense
NM_001354900.2:c.-42-11341A>G		intron variant
NM_001354901.2:c.-42-11341A>G		intron variant
NM_001354902.2:c.166-11341A>G		intron variant
NM_001354903.2:c.95A>G	NP_001341832.1:p.Asn32Ser	missense
NM_001354904.2:c.61-11341A>G		intron variant
NM_001354905.2:c.-42-11341A>G		intron variant
NM_001354906.2:c.-941A>G		5 prime UTR
NC_000005.10:g.112754985A>G
NC_000005.9:g.112090682A>G
NG_008481.4:g.67465A>G
LRG_130:g.67465A>G
LRG_130t1:c.95A>G

... more HGVS ... less HGVS

Protein change

N32S

Other names

Canonical SPDI

NC_000005.10:112754984: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.

0.00020 (G)

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

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA051346 dbSNP: rs539108537 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 specified	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jun 3, 2024	RCV000202147.18
Familial adenomatous polyposis 1	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000204603.22
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jun 7, 2022	RCV000569857.18
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jul 29, 2024	RCV000656743.18
Neoplasm of stomach	Uncertain significance (1)	no assertion criteria provided	Jan 25, 2018	RCV000677775.8
Classic or attenuated familial adenomatous polyposis	Likely benign (1)	criteria provided, single submitter	Dec 18, 2023	RCV003997044.2

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 (Jan 29, 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: SCV000259432.12 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 26976419‚ 29237405 Comment: This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 32 of the APC protein (p.Asn32Ser). … (more) This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 32 of the APC protein (p.Asn32Ser). This variant is present in population databases (rs539108537, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and colon cancer (PMID: 26976419, 29237405). ClinVar contains an entry for this variant (Variation ID: 218010). 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)
Likely benign (Jun 07, 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: SCV000667217.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 32658311 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 29, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292446.17 First in ClinVar: Jul 24, 2016 Last updated: Sep 16, 2024	Comment: In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or breast cancer, and also in controls … (more) In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or breast cancer, and also in controls in a case-control study of biliary tract cancer (PMID: 18199528, 26976419, 29237405, 32658311, 36243179); This variant is associated with the following publications: (PMID: 29237405, 26976419, 26900293, 27908614, 32658311, 18199528, 36243179) (less)
Likely benign (Jun 16, 2016)	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: SCV000910900.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial adenomatous polyposis 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136868.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Nov 05, 2018)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000887557.3 First in ClinVar: Jul 09, 2018 Last updated: Jan 01, 2022	Publications: PubMed (3) PubMed: 26976419‚ 26900293‚ 29237405
Uncertain significance (Dec 28, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529596.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The APC c.95A>G (p.N32S) variant has been reported in heterozygosity in at least 4 individuals with breast and colorectal cancer (PMID: 26976419, 26900293, 29237405, 32658311), … (more) The APC c.95A>G (p.N32S) variant has been reported in heterozygosity in at least 4 individuals with breast and colorectal cancer (PMID: 26976419, 26900293, 29237405, 32658311), but has also been reported in healthy controls from a colorectal study (PMID: 32658311). It was observed in 5/24970 chromosomes of the African/African American subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 218010). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (4) PubMed: 26976419‚ 26900293‚ 29237405‚ 32658311
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: SCV002010852.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Likely benign (Feb 06, 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: SCV004243222.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Likely Benign (Dec 18, 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: SCV004841694.1 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)	Number of individuals with the variant: 10
Likely benign (Jun 03, 2024)	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: SCV000916487.2 First in ClinVar: Jun 03, 2019 Last updated: Sep 16, 2024	Publications: PubMed (7) PubMed: 26900293‚ 26976419‚ 28380452‚ 32658311‚ 29237405‚ 36243179‚ 33569305 Comment: Variant summary: APC c.95A>G (p.Asn32Ser) results in a conservative amino acid change located in the adenomatous polyposis coli, N-terminal dimerisation domain (IPR032038) of the encoded … (more) Variant summary: APC c.95A>G (p.Asn32Ser) results in a conservative amino acid change located in the adenomatous polyposis coli, N-terminal dimerisation domain (IPR032038) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 252236 control chromosomes (gnomAD, Akcay_2020). The variant allele was found at a frequency of 4.3e-05 in 1614796 control chromosomes, predominantly at a frequency of 0.00019 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). The variant has been found as a germline and somatic variant in patients with various cancers including but not limited to colorectal cancer, non-small cell lung cancer, and breast cancer without strong evidence for or against pathogenicity (example: Chang_2016, Lv_2017, Tung_2016, Lee_2017, Akcay_2020, Pavan_2021) as well as in controls (Akcay_2020, Okawa_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26900293, 26976419, 28380452, 32658311, 29237405, 36243179, 33569305). ClinVar contains an entry for this variant (Variation ID: 218010). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Uncertain significance (-)	no assertion criteria provided Method: research	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257039.1 First in ClinVar: Nov 21, 2015 Last updated: Nov 21, 2015	Number of individuals with the variant: 1
Uncertain significance (Jan 25, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Neoplasm of stomach Affected status: yes Allele origin: germline	3DMed Clinical Laboratory Inc Accession: SCV000803931.1 First in ClinVar: Aug 27, 2018 Last updated: Aug 27, 2018
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Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 32 of the APC protein (p.Asn32Ser). This variant is present in population databases (rs539108537, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and colon cancer (PMID: 26976419, 29237405). ClinVar contains an entry for this variant (Variation ID: 218010). 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:

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:

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or breast cancer, and also in controls in a case-control study of biliary tract cancer (PMID: 18199528, 26976419, 29237405, 32658311, 36243179); This variant is associated with the following publications: (PMID: 29237405, 26976419, 26900293, 27908614, 32658311, 18199528, 36243179)

Comment:

Variant summary: APC c.95A>G (p.Asn32Ser) results in a conservative amino acid change located in the adenomatous polyposis coli, N-terminal dimerisation domain (IPR032038) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 252236 control chromosomes (gnomAD, Akcay_2020). The variant allele was found at a frequency of 4.3e-05 in 1614796 control chromosomes, predominantly at a frequency of 0.00019 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). The variant has been found as a germline and somatic variant in patients with various cancers including but not limited to colorectal cancer, non-small cell lung cancer, and breast cancer without strong evidence for or against pathogenicity (example: Chang_2016, Lv_2017, Tung_2016, Lee_2017, Akcay_2020, Pavan_2021) as well as in controls (Akcay_2020, Okawa_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26900293, 26976419, 28380452, 32658311, 29237405, 36243179, 33569305). ClinVar contains an entry for this variant (Variation ID: 218010). Based on the evidence outlined above, the variant was classified as likely benign.

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
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer.	Okawa Y	Journal of hepatology	2023	PMID: 36243179
Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome.	Pavan A	Translational lung cancer research	2021	PMID: 33569305
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.	Akcay IM	International journal of cancer	2021	PMID: 32658311
Prevalence and characteristics of hereditary non-polyposis colorectal cancer (HNPCC) syndrome in immigrant Asian colorectal cancer patients.	Lee J	BMC cancer	2017	PMID: 29237405
Detection of oncogenic mutations in resected bronchial margins by next-generation sequencing indicates early relapse in stage IA lung adenocarcinoma patients.	Lv T	Oncotarget	2017	PMID: 28380452
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.	Tung N	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2016	PMID: 26976419
Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients.	Chang YC	World journal of gastroenterology	2016	PMID: 26900293

Text-mined citations for rs539108537 ...

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.95A>G (p.Asn32Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs539108537 ...