rs587781935

chr5-112840329-A-Gchr5-112840329-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000038.6(APC):c.4735A>G(p.Ile1579Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 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. I1579F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000038.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4735A>G	p.Ile1579Val	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4735A>G	p.Ile1579Val	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 66 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 25, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 141684). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 18199528). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1579 of the APC protein (p.Ile1579Val). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2020

The p.I1579V variant (also known as c.4735A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4735. The isoleucine at codon 1579 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in patients whose clinical history is consistent with attenuated familial adenomatous polyposis (Ambry internal data). In one study, p.I1579V was detected in one individual with multiple colorectal adenomas (total number of adenomas unknown) and 0/969 unrelated healthy controls (Azzopardi D et al. Cancer Res. 2008 Jan 15;68(2):358-63). Overall, this study found a higher frequency of rare, non-synonymous changes in individuals with multiple adenomas. It has been suggested that this missense alteration within a SAMP-repeat region might disrupt APC secondary structure related to Axin binding (Minde DP et al. Mol Cancer. 2011 Aug 22;10:101). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.75	N;N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.99	D;D
Vest4		0.83
MutPred		0.84		Gain of catalytic residue at I1579 (P = 8e-04);Gain of catalytic residue at I1579 (P = 8e-04);
MVP		0.97
ClinPred		0.77	D
GERP RS		6.2
Varity_R		0.72
gMVP		0.62

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: rs587781935; hg19: chr5-112176026;