5-112767228-T-G

Position:

• chr5-112767228-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000038.6(APC):​c.260T>G​(p.Leu87Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.70

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32527056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.260T>G	p.Leu87Arg	missense_variant	4/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.260T>G	p.Leu87Arg	missense_variant	4/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251452 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2020

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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with APC-related conditions. This variant is present in population databases (rs777456713, ExAC 0.01%). This sequence change replaces leucine with arginine at codon 87 of the APC protein (p.Leu87Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The p.L87R variant (also known as c.260T>G), located in coding exon 3 of the APC gene, results from a T to G substitution at nucleotide position 260. The leucine at codon 87 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. 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	Benign	0.15
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;D;D;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Benign	0.90	.;.;L;L;.
MutationTaster	Benign	0.68	N;N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.016	D;T;T;T;T
Sift4G	Benign	0.099	T;T;T;T;T
Polyphen		0.56	.;.;P;P;.
Vest4		0.76, 0.94
MutPred		0.28		Gain of loop (P = 0.0166);.;Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.96
ClinPred		0.41	T
GERP RS		5.5
Varity_R		0.29
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777456713; hg19: chr5-112102925;