VCV000350415.26 - ClinVar

NM_000038.6(APC):c.5840C>G (p.Thr1947Ser)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance (5); Likely benign (2)

7 out of 7 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000038.6(APC):c.5840C>G (p.Thr1947Ser)

Variation ID: 350415 Accession: VCV000350415.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q22.2 5: 112841434 (GRCh38) [ NCBI UCSC ] 5: 112177131 (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	May 3, 2025	Aug 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.5840C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Thr1947Ser	missense
NM_001127510.3:c.5840C>G	NP_001120982.1:p.Thr1947Ser	missense
NM_001127511.3:c.5786C>G	NP_001120983.2:p.Thr1929Ser	missense
NM_001354895.2:c.5840C>G	NP_001341824.1:p.Thr1947Ser	missense
NM_001354896.2:c.5894C>G	NP_001341825.1:p.Thr1965Ser	missense
NM_001354897.2:c.5870C>G	NP_001341826.1:p.Thr1957Ser	missense
NM_001354898.2:c.5765C>G	NP_001341827.1:p.Thr1922Ser	missense
NM_001354899.2:c.5756C>G	NP_001341828.1:p.Thr1919Ser	missense
NM_001354900.2:c.5717C>G	NP_001341829.1:p.Thr1906Ser	missense
NM_001354901.2:c.5663C>G	NP_001341830.1:p.Thr1888Ser	missense
NM_001354902.2:c.5567C>G	NP_001341831.1:p.Thr1856Ser	missense
NM_001354903.2:c.5537C>G	NP_001341832.1:p.Thr1846Ser	missense
NM_001354904.2:c.5462C>G	NP_001341833.1:p.Thr1821Ser	missense
NM_001354905.2:c.5360C>G	NP_001341834.1:p.Thr1787Ser	missense
NM_001354906.2:c.4991C>G	NP_001341835.1:p.Thr1664Ser	missense
NC_000005.10:g.112841434C>G
NC_000005.9:g.112177131C>G
NG_008481.4:g.153914C>G
LRG_130:g.153914C>G

... more HGVS ... less HGVS

Protein change

T1947S, T1929S, T1664S, T1821S, T1846S, T1888S, T1919S, T1922S, T1957S, T1787S, T1906S, T1856S, T1965S

Other names

Canonical SPDI

NC_000005.10:112841433:C:G

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.

The Genome Aggregation Database (gnomAD) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA043197 dbSNP: rs575724078 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	17016	17167

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.
APC-Associated Polyposis Disorders	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000362266.13
Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Apr 24, 2024	RCV000775335.18
not specified	Uncertain significance (1)	criteria provided, single submitter	Mar 13, 2019	RCV001821073.11
Familial adenomatous polyposis 1	Uncertain significance (1)	criteria provided, single submitter	Mar 15, 2024	RCV002520290.10
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 5, 2023	RCV003317196.8
Classic or attenuated familial adenomatous polyposis	Uncertain significance (1)	criteria provided, single submitter	Aug 13, 2024	RCV004806281.1

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.	Expand all rows Collapse all rows 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.
Likely benign (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	APC-Associated Polyposis Disorders	Illumina Laboratory Services, Illumina Accession: SCV000452030.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Mar 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial adenomatous polyposis 1	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000932522.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025	Comment: show This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1947 of the APC protein (p.Thr1947Ser). This variant is present in population databases (rs575724078, gnomAD 0.02%). 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: 350415). 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Apr 24, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000909606.5 First in ClinVar: May 20, 2019 Last updated: May 03, 2025	Comment: show This missense variant replaces threonine with serine at codon 1947 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. This variant has been identified in 5/250460 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Uncertain significance (Mar 13, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Genetic Services Laboratory, University of Chicago Accession: SCV002068675.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Uncertain significance (Apr 05, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV004021624.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (May 02, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV002647760.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain Significance (Aug 13, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Classic or attenuated familial adenomatous polyposis (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV005426282.1 First in ClinVar: Dec 14, 2024 Last updated: Dec 14, 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)	Comment: show This missense variant replaces threonine with serine at codon 1947 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. This variant has been identified in 5/250460 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 2 Zygosity: 2 Single Heterozygotes

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1947 of the APC protein (p.Thr1947Ser). This variant is present in population databases (rs575724078, gnomAD 0.02%). 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: 350415). 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 missense variant replaces threonine with serine at codon 1947 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. This variant has been identified in 5/250460 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:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528)

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:

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 rs575724078 ...

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 Apr 13, 2026