rs1554081691

chr5-112827180-G-Achr5-112827180-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM5 BP4

The NM_000038.6(APC):c.1481G>A(p.Ser494Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S494G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 5.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a helix (size 17) in uniprot entity APC_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000038.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-112827178-CAG-CT is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.38752064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1481G>A	p.Ser494Asn	missense_variant	12/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1481G>A	p.Ser494Asn	missense_variant	12/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461562 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2023	This missense variant replaces serine with asparagine at codon 494 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 suspected of Lynch Syndrome (PMID: 25980754). This variant has not been identified 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2022	The p.S494N variant (also known as c.1481G>A), located in coding exon 11 of the APC gene, results from a G to A substitution at nucleotide position 1481. The serine at codon 494 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps. (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 494 of the APC protein (p.Ser494Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 490207). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 28, 2017

Variant summary: The APC c.1481G>A (p.Ser494Asn) variant involves the alteration of a conserved nucleotide, resulting in a missense change located in the Armadillo repeat and Armadillo-like helical domain (InterPro) . 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was absent in the control population dataset of gnomAD in 246040 control chromosomes. The variant was reported in one individual undergoing genetic testing for Lynch syndrome without strong evidence for or against causality (Yurgelun_2015). Taken together, this variant is classified as VUS. -

Classic or attenuated familial adenomatous polyposis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 03, 2023

This missense variant replaces serine with asparagine at codon 494 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 individuals suspected of with Lynch Syndrome in the literature (PMID: 25980754). This variant has not been identified 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	23
Dann	Benign	0.77
Eigen	Benign	-0.089
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;.;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.6	N;N;N;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.58	T;T;T;T;.
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.016	.;B;B;.;.
Vest4		0.25, 0.25
MutPred		0.47		.;Loss of catalytic residue at S494 (P = 0.0213);Loss of catalytic residue at S494 (P = 0.0213);Loss of catalytic residue at S494 (P = 0.0213);.;
MVP		0.74
ClinPred		0.78	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554081691; hg19: chr5-112162877;