rs587780545

chr5-112792489-G-Achr5-112792489-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000038.6(APC):c.689G>A(p.Arg230His) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 6.92

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_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000038.6
• BS2: High AC in GnomAdExome at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.689G>A	p.Arg230His	missense_variant	7/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.689G>A	p.Arg230His	missense_variant	7/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251200 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135762

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460262 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 726458

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: The APC c.689G>A (p.Arg230His) variant involves the alteration of a conserved nucleotide. Arg230 is conserved through species and located in the Adenomatous polyposis coli protein domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/120512 control chromosomes at a frequency of 0.0000664, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 11, 2023	The frequency of this variant in the general population, 0.000047 (6/129016 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colon cancer (PMID: 28125075 (2017)) and uterine carcinosarcoma (PMID: 29684080 (2018)). It was also reported in an individual with either diagnosed or suspected Familial adenomatous polyposis (FAP) (PMID: 35189564 (2022)). Analysis of this variant using a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded a prediction that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Ghazani 2017); This variant is associated with the following publications: (PMID: 28125075) -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 02, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2023	This missense variant replaces arginine with histidine at codon 230 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal, uterine, or pancreatic cancer (PMID: 28125075, 29684080, 32980694), as well as in 37 unaffected individuals in a pancreatic case control study (PMID: 32980694). This variant has been identified in 12/282562 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2022	- -

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the APC protein (p.Arg230His). This variant is present in population databases (rs587780545, gnomAD 0.01%). This missense change has been observed in individual(s) with colon cancer (PMID: 28125075, 35189564). ClinVar contains an entry for this variant (Variation ID: 132732). 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	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;D;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.92	N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.65
MutPred		0.26		Loss of loop (P = 0.0153);Loss of loop (P = 0.0153);Loss of loop (P = 0.0153);
MVP		0.88
ClinPred		0.40	T
GERP RS		5.2
Varity_R		0.52
gMVP		0.35

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: rs587780545; hg19: chr5-112128186; COSMIC: COSV57328086;