rs876658835

chr5-112840818-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000038.6(APC):c.5224C>T(p.Arg1742Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1742H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 4.86

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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.5224C>T	p.Arg1742Cys	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.5224C>T	p.Arg1742Cys	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461804 Hom.: 0 Cov.: 64 AF XY: 0.00000550 AC XY: 4 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000480

Bravo AF: 0.00000756

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	Ambry Genetics	Jun 07, 2023	The p.R1742C variant (also known as c.5224C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 5224. The arginine at codon 1742 is replaced by cysteine, an amino acid with highly 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	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2023	This missense variant replaces arginine with cysteine at codon 1742 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 34347074) and in unaffected individuals (PMID: 32980694). 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with colorectal cancer (Biscaglia et al., 2021); This variant is associated with the following publications: (PMID: 18199528, 34347074) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 16, 2020	- -

APC-Associated Polyposis Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1742 of the APC protein (p.Arg1742Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 34347074). ClinVar contains an entry for this variant (Variation ID: 230908). 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. -

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

Dec 01, 2023

This missense variant replaces arginine with cysteine at codon 1742 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 34347074) and in unaffected individuals (PMID: 32980694). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.38		Loss of MoRF binding (P = 0.0055);Loss of MoRF binding (P = 0.0055);
MVP		0.97
ClinPred		0.84	D
GERP RS		6.2
Varity_R		0.36
gMVP		0.56

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: rs876658835; hg19: chr5-112176515; COSMIC: COSV57323749; COSMIC: COSV57323749;