chr5-112840951-G-A

Position:

• chr5-112840951-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000038.6(APC):​c.5357G>A​(p.Arg1786Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.03

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22443822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.5357G>A	p.Arg1786Lys	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.5357G>A	p.Arg1786Lys	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461064 Hom.: 0 Cov.: 54 AF XY: 0.00 AC XY: 0 AN XY: 726878

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 11, 2024	The p.R1786K variant (also known as c.5357G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 5357. The arginine at codon 1786 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 03, 2019	- -

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 411381). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1786 of the APC protein (p.Arg1786Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 03, 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 individual(s) with breast cancer (Tung et al., 2016); This variant is associated with the following publications: (PMID: 18199528, 26976419) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.091
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.19
Sift	Benign	0.20	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.24
MutPred		0.21		Gain of methylation at R1786 (P = 0.013);Gain of methylation at R1786 (P = 0.013);
MVP		0.81
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.098
gMVP		0.58

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: rs944674770; hg19: chr5-112176648;