5-112838901-A-T

Position:

• chr5-112838901-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000038.6(APC):​c.3307A>T​(p.Arg1103Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.38

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.3307A>T	p.Arg1103Trp	missense_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3307A>T	p.Arg1103Trp	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1103 of the APC protein (p.Arg1103Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 29518763). ClinVar contains an entry for this variant (Variation ID: 383369). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 02, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 04, 2023	The p.R1103W variant (also known as c.3307A>T), located in coding exon 15 of the APC gene, results from an A to T substitution at nucleotide position 3307. The arginine at codon 1103 is replaced by tryptophan, an amino acid with dissimilar properties. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 18, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2016

The R1103W variant in the APC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1103W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1103W variant is a non-conservative amino acid substitution, which occurs at a position within the 15-amino acid repeat β-catenin binding domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1103W as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D;D;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.0	.;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;N;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.74, 0.82
MutPred		0.37		.;Loss of disorder (P = 0.0013);Loss of disorder (P = 0.0013);Loss of disorder (P = 0.0013);
MVP		0.97
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.36
gMVP		0.54

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: rs1057521600; hg19: chr5-112174598;