rs1554081633

Positions:

• chr5-112827110-G-A
• chr5-112827110-G-C
• chr5-112827110-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000038.6(APC):​c.1411G>A​(p.Gly471Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. G471E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1411G>A	p.Gly471Arg	missense_variant, splice_region_variant	12/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1411G>A	p.Gly471Arg	missense_variant, splice_region_variant	12/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Aug 23, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 537508). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 471 of the APC protein (p.Gly471Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2024

The p.G471R variant (also known as c.1411G>A), located in coding exon 11 of the APC gene, results from a G to A substitution at nucleotide position 1411. The glycine at codon 471 is replaced by arginine, an amino acid with 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. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;D;D;D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	1.7	.;L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.7	D;D;D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;T
Polyphen		1.0	.;D;D;.;.
Vest4		0.95, 0.87
MutPred		0.67		.;Gain of methylation at G471 (P = 0.0397);Gain of methylation at G471 (P = 0.0397);Gain of methylation at G471 (P = 0.0397);.;
MVP		0.95
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.87

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: rs1554081633; hg19: chr5-112162807; COSMIC: COSV57336849; COSMIC: COSV57336849;