5-112815543-A-G

Variant names:

• chr5-112815543-A-G
• rs587780611
• NM_000038.6:c.883A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000038.6(APC):​c.883A>G​(p.Ser295Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S295I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.800
• Publications: 12 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.085464716).
• BP6: Variant 5-112815543-A-G is Benign according to our data. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729. Variant chr5-112815543-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 135729.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.883A>G	p.Ser295Gly	missense_variant	Exon 9 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.883A>G	p.Ser295Gly	missense_variant	Exon 9 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251104 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460198 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726482

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110894

Other (OTH) AF: 0.0000166 AC: 1 AN: 60256

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000340 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Mar 06, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

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 glycine, which is neutral and non-polar, at codon 295 of the APC protein (p.Ser295Gly). This variant is present in population databases (rs587780611, gnomAD 0.02%). This missense change has been observed in individual(s) with biliary tract cancer and/or colorectal cancer (PMID: 3193653, 36243179). ClinVar contains an entry for this variant (Variation ID: 135729). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

not specified Uncertain:1 Benign:1

Aug 02, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.883A>G (p.Ser295Gly) results in a non-conservative amino acid change in 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 2e-05 in 251372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.883A>G has been reported in the literature in individuals in the lieterature affected with gastric cancer (Ge_2017) and schizophrenia (Yang_2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Apr 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with glycine at codon 295 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 been reported in an individual affected with colorectal cancer (PMID: 33193653), breast cancer (PMID: 29684080), and in cases and controls in a biliary tract cancer study (PMID: 36243179). This variant has been identified in 6/282508 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. -

Oct 26, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:1

Feb 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer in The Cancer Genome Atlas (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 28195569, 32980694, 29684080) -

Ovarian cancer Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.41	.;T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.60	T;.;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.2	.;L;L;.
PhyloP100		0.80
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.87	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.062	.;B;B;.
Vest4		0.28, 0.31
MutPred		0.31		.;Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.84
ClinPred		0.023	T
GERP RS		1.3
Varity_R		0.10
gMVP		0.22
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.080		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: rs587780611; hg19: chr5-112151240;