5-112842463-C-T

Position:

• chr5-112842463-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000038.6(APC):​c.6869C>T​(p.Ser2290Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.16

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27365053).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.6869C>T	p.Ser2290Phe	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.6869C>T	p.Ser2290Phe	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+13491C>T		intron_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461720 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727158

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000637 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 01, 2024	The p.S2290F variant (also known as c.6869C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 6869. The serine at codon 2290 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not well 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:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2022

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2290 of the APC protein (p.Ser2290Phe). This variant is not present in population databases (gnomAD no frequency). 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: 486761). This variant has not been reported in the literature in individuals affected with APC-related conditions. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 17, 2019

- -

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

Sep 23, 2024

- -

APC-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2024

The APC c.6869C>T variant is predicted to result in the amino acid substitution p.Ser2290Phe. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/486761/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.000096
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.0020	B;B
Vest4		0.39
MutPred		0.32		Loss of phosphorylation at S2290 (P = 0.0037);Loss of phosphorylation at S2290 (P = 0.0037);
MVP		0.85
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.16
gMVP		0.52

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: rs1554087810; hg19: chr5-112178160;