rs1114167617

Variant names:

• chr5-112838677-G-A
• rs1114167617
• NM_000038.6:c.3083G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112838677-G-A
• chr5-112838677-G-C
• chr5-112838677-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2_Supporting PS4_Moderate PM5_Supporting PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6:c.3083G>A variant in APC is a missense variant predicted to cause the substitution of serine to asparagine at amino acid position 1028 (p.Ser1028Asn). This variant has been reported in 4 probands/families meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate; internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and one individual with colorectal cancer in the family history (internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). This variant has been reported to segregate with FAP in 5 meioses in 2 families (PP1_Moderate; internal data Ambry Genetics and Peter MacCallum Cancer Centre, Victoria, Australia). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants (c.3084T>A and c.3083G>T) in the same codon leading to a different amino acid change at this position (p.Ser1028Arg; p.Ser1028Ile) have been classified as Likely Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PS4_Moderate, PP1_Moderate, PM2_Supporting and PM5_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16028084/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.36
• Publications: 3 publications found

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.3083G>A	p.Ser1028Asn	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3083G>A	p.Ser1028Asn	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+9705G>A		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2 Uncertain:1

May 19, 2025

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000038.6:c.3083G>A variant in APC is a missense variant predicted to cause the substitution of serine to asparagine at amino acid position 1028 (p.Ser1028Asn). This variant has been reported in 4 probands/families meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate; internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and one individual with colorectal cancer in the family history (internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). This variant has been reported to segregate with FAP in 5 meioses in 2 families (PP1_Moderate; internal data Ambry Genetics and Peter MacCallum Cancer Centre, Victoria, Australia). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants (c.3084T>A and c.3083G>T) in the same codon leading to a different amino acid change at this position (p.Ser1028Arg; p.Ser1028Ile) have been classified as Likely Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PS4_Moderate, PP1_Moderate, PM2_Supporting and PM5_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). -

Apr 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1028 of the APC protein (p.Ser1028Asn). This variant is not present in population databases (gnomAD no frequency). 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: 428186). 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. 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. -

Mar 12, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 06, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1028N pathogenic mutation (also known as c.3083G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 3083. The serine at codon 1028 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Personal communication). This alteration was shown to segregate with disease in one family (Ambry internal data). A nearby amino acid, APC p.N1026, likely interacts directly with APC p.S1028. A missense alteration at the nearby amino acid, APC p.N1026S, which was also shown to segregate with AFAP, is impaired in its ability to bind to β-Catenin and, thus, impaired in reducing β-Catenin signaling (Menéndez M et al. Gastroenterology. 2008 Jan;134:56-64; Kohler EM et al. Hum. Mol. Genet. 2008 Jul;17:1978-87). Internal structural analysis shows that this variant (p.S1028N) lies on the protein interface that is indicated to be important for β-Catenin binding (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D;D;D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	.;N;N;.
PhyloP100		9.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.90, 0.66
MutPred		0.72		.;Loss of phosphorylation at S1028 (P = 0.1007);Loss of phosphorylation at S1028 (P = 0.1007);Loss of phosphorylation at S1028 (P = 0.1007);
MVP		0.91
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.77
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1114167617; hg19: chr5-112174374;