VCV000133530.44 - ClinVar

NM_000038.6(APC):c.4420G>A (p.Ala1474Thr)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Benign

for Familial adenomatous polyposis 1

Classification is based on the expert panel submission

Feb 2023 by ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Vari…

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000038.6(APC):c.4420G>A (p.Ala1474Thr)

Variation ID: 133530 Accession: VCV000133530.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q22.2 5: 112840014 (GRCh38) [ NCBI UCSC ] 5: 112175711 (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	Jun 9, 2014	Jun 20, 2026	Feb 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000038.6:c.4420G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000029.2:p.Ala1474Thr	missense
NM_001127510.3:c.4420G>A	NP_001120982.1:p.Ala1474Thr	missense
NM_001127511.3:c.4366G>A	NP_001120983.2:p.Ala1456Thr	missense
NM_001354895.2:c.4420G>A	NP_001341824.1:p.Ala1474Thr	missense
NM_001354896.2:c.4474G>A	NP_001341825.1:p.Ala1492Thr	missense
NM_001354897.2:c.4450G>A	NP_001341826.1:p.Ala1484Thr	missense
NM_001354898.2:c.4345G>A	NP_001341827.1:p.Ala1449Thr	missense
NM_001354899.2:c.4336G>A	NP_001341828.1:p.Ala1446Thr	missense
NM_001354900.2:c.4297G>A	NP_001341829.1:p.Ala1433Thr	missense
NM_001354901.2:c.4243G>A	NP_001341830.1:p.Ala1415Thr	missense
NM_001354902.2:c.4147G>A	NP_001341831.1:p.Ala1383Thr	missense
NM_001354903.2:c.4117G>A	NP_001341832.1:p.Ala1373Thr	missense
NM_001354904.2:c.4042G>A	NP_001341833.1:p.Ala1348Thr	missense
NM_001354905.2:c.3940G>A	NP_001341834.1:p.Ala1314Thr	missense
NM_001354906.2:c.3571G>A	NP_001341835.1:p.Ala1191Thr	missense
NC_000005.10:g.112840014G>A
NC_000005.9:g.112175711G>A
NG_008481.4:g.152494G>A
LRG_130:g.152494G>A
LRG_130t1:c.4420G>A

... more HGVS ... less HGVS

Protein change

A1456T, A1474T, A1383T, A1449T, A1191T, A1348T, A1314T, A1373T, A1433T, A1446T, A1492T, A1415T, A1484T

Other names

p.A1474T:GCT>ACT
NM_000038.6(APC):c.4420G>A

Canonical SPDI

NC_000005.10:112840013:G:A

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.

0.00260 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00030

The Genome Aggregation Database (gnomAD), exomes 0.00077

Exome Aggregation Consortium (ExAC) 0.00091

1000 Genomes Project 0.00260

1000 Genomes Project 30x 0.00265

The Genome Aggregation Database (gnomAD) 0.00299

The Genome Aggregation Database (gnomAD) 0.00324

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00338

Trans-Omics for Precision Medicine (TOPMed) 0.00359

Links

ClinGen: CA009532 dbSNP: rs139387758 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	16905	17056

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	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Apr 25, 2017	RCV000120040.23
Colorectal adenoma	Uncertain significance (1)	no assertion criteria provided	Jun 1, 2014	RCV000148366.10
Hereditary cancer-predisposing syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Sep 19, 2024	RCV000129100.17
APC-Associated Polyposis Disorders	Likely benign (1)	criteria provided, single submitter	Nov 29, 2018	RCV000321870.12
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Aug 1, 2025	RCV000759431.21
Familial adenomatous polyposis 1	Benign (4)	reviewed by expert panel	Feb 26, 2023	RCV000987573.19
Carcinoma of colon	Likely benign (1)	no assertion criteria provided	-	RCV001358624.8
Classic or attenuated familial adenomatous polyposis	Benign (1)	criteria provided, single submitter	Feb 5, 2024	RCV003997332.2

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.	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.
Benign (Feb 26, 2023) C Contributing to aggregate classification	reviewed by expert panel (ClinGen InSiGHT HCCP VCEP ACMG Specifications APC V1)	Familial adenomatous polyposis 1 (Autosomal dominant inheritance)	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel FDA Recognized Database Accession: SCV003836603.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/84be63ca-6205-415b-8aa7-b32b28a56daf Comment: show The c.4420G>A variant in APC is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid position 1474 (p.Ala1474Thr). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 1.13% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel’s (HCCP VCEP) threshold (0.1%) for BA1, and therefore meets this criterion (BA1). Functional study of beta-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as wild type (BS3_Supporting; PMID: 18199528). Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP1, BS3_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely benign (Aug 01, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV006328927.6 First in ClinVar: Sep 22, 2025 Last updated: Jun 20, 2026	Comment: show APC: BS1 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Likely benign (Oct 27, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	not specified	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602521.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Nov 29, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	APC-Associated Polyposis Disorders	Illumina Laboratory Services, Illumina Accession: SCV000452012.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (8) PubMed: 18199528‚ 21859464‚ 24055113‚ 24728327‚ 2472832‚ 24861525‚ 25637381‚ 26332594 Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (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

Benign (Feb 05, 2024) N Not 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: SCV004837932.1 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)	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: 184 Zygosity: 4 Homozygotes, 180 Single Heterozygotes

Benign (Jan 04, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000183811.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: show This alteration is classified as 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

Benign (Apr 10, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Familial adenomatous polyposis 1	Myriad Genetics, Inc. Accession: SCV005084458.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: show This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely benign (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Autosomal dominant inheritance)	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005219839.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Observation: 1 Collection method: not provided Allele origin: germline Affected status: yes Observation 1 Collection method: not provided Allele origin: germline Affected status: yes

Benign (Feb 04, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial adenomatous polyposis 1	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000252587.14 First in ClinVar: Oct 11, 2015 Last updated: Feb 15, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 25, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	PreventionGenetics, part of Exact Sciences Accession: SCV000805409.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (May 28, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Familial adenomatous polyposis 1	Mendelics Accession: SCV001136913.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Mar 21, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Hereditary cancer-predisposing syndrome	Sema4, Sema4 Accession: SCV002534272.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Benign (Dec 04, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000167009.12 First in ClinVar: Jun 09, 2014 Last updated: Mar 04, 2023	Comment: show This variant is associated with the following publications: (PMID: 18199528, 24728327, 24055113, 24861525, 25637381, 21859464, 26332594) (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

Benign (Jul 08, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888745.4 First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024	Publications: PubMed (11) PubMed: 11823972‚ 18199528‚ 21859464‚ 24055113‚ 24728327‚ 24861525‚ 25178641‚ 25356985‚ 25637381‚ 26332594‚ 33503190 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Sep 19, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000902635.2 First in ClinVar: May 20, 2019 Last updated: May 03, 2025	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 (Jun 01, 2014) N Not contributing to aggregate classification	no assertion criteria provided	Colorectal adenoma (Autosomal dominant inheritance)	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190058.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	Carcinoma of colon	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001554414.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: show The APC p.Ala1474Thr variant was identified in 1 of 1382 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal polyps (Azzopardi, 2008). The variant was also identified in dbSNP (ID: rs139387758 as With Uncertain significance allele), ClinVar (3x as benign, 2x as likely benign, 1x as a variant of uncertain significance), Cosmic (2x), LOVD 3.0 (1x as not classified), and UMD-LSDB (1x). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 290 of 276830 chromosomes (2 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 270 of 24026 chromosomes (freq: 0.01), Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European Non-Finnish in 4 of 126384 chromosomes (freq: 0.00003), and SouthAsian in 1 of 30774 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Ala1474 residue is moderately conserved in mammals, although 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 1

not provided (Sep 19, 2013) N Not contributing to aggregate classification	no classification provided	AllHighlyPenetrant	ITMI Accession: SCV000084173.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation: 7 Observation 1 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Whole_cohort Platform type: next-gen sequencing Platform name: Complete Genomics Observation 2 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African Platform type: next-gen sequencing Platform name: Complete Genomics Observation 3 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African_European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 4 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Central_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 5 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: East_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 6 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 7 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Hispanic Platform Type: next-gen sequencing Platform Name: Complete Genomics

Comment:

The c.4420G>A variant in APC is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid position 1474 (p.Ala1474Thr). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 1.13% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel’s (HCCP VCEP) threshold (0.1%) for BA1, and therefore meets this criterion (BA1). Functional study of beta-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as wild type (BS3_Supporting; PMID: 18199528). Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP1, BS3_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as 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:

The APC p.Ala1474Thr variant was identified in 1 of 1382 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal polyps (Azzopardi, 2008). The variant was also identified in dbSNP (ID: rs139387758 as With Uncertain significance allele), ClinVar (3x as benign, 2x as likely benign, 1x as a variant of uncertain significance), Cosmic (2x), LOVD 3.0 (1x as not classified), and UMD-LSDB (1x). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 290 of 276830 chromosomes (2 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 270 of 24026 chromosomes (freq: 0.01), Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European Non-Finnish in 4 of 126384 chromosomes (freq: 0.00003), and SouthAsian in 1 of 30774 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Ala1474 residue is moderately conserved in mammals, although 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The mutational repertoire of uterine sarcomas and carcinosarcomas in a Brazilian cohort: A preliminary study.	da Costa LT	Clinics (Sao Paulo, Brazil)	2021	PMID: 33503190
Identification of Medically Actionable Secondary Findings in the 1000 Genomes.	Olfson E	PloS one	2015	PMID: 26332594
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Validation of a next-generation-sequencing cancer panel for use in the clinical laboratory.	Simen BB	Archives of pathology & laboratory medicine	2015	PMID: 25356985
Molecular profiling of infiltrating urothelial carcinoma of bladder and nonbladder origin.	Millis SZ	Clinical genitourinary cancer	2015	PMID: 25178641
Genetic analysis in APC, KRAS, and TP53 in patients with stomach and colon cancer.	Palacio-Rúa KA	Revista de gastroenterologia de Mexico	2014	PMID: 24861525
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Actionable, pathogenic incidental findings in 1,000 participants' exomes.	Dorschner MO	American journal of human genetics	2013	PMID: 24055113
Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?	Minde DP	Molecular cancer	2011	PMID: 21859464
Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas.	Azzopardi D	Cancer research	2008	PMID: 18199528
Fibromatosis of the breast and mutations involving the APC/beta-catenin pathway.	Abraham SC	Human pathology	2002	PMID: 11823972
31P NMR spectra of ethidium, quinacrine, and daunomycin complexes with poly(adenylic acid).poly(uridylic acid) RNA duplex and calf thymus DNA.	Gorenstein DG	Biochemistry	1989	PMID: 2472832
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/84be63ca-6205-415b-8aa7-b32b28a56daf	-	-	-	-
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Text-mined citations for rs139387758 ...

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 Jun 20, 2026