rs1114167617

chr5-112838677-G-Achr5-112838677-G-Cchr5-112838677-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Strong

The NM_000038.6(APC):c.3083G>A(p.Ser1028Asn) variant causes a missense 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. 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. S1028I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 9.36

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000038.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-112838677-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 469904.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 5-112838677-G-A is Pathogenic according to our data. Variant chr5-112838677-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 428186.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.3083G>A	p.Ser1028Asn	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.3083G>A	p.Ser1028Asn	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 25, 2023	The c.3083G>A variant in APC is a missense variant predicted to cause the substitution of serine to asparagine at amino acid position 1028 (p.Ser1028Asn). This alteration has been identified in 2 families with attenuated FAP worth 1 phenotype points (PS4_supporting). Two other missense variants (c.3084T>A and c.3083G>T) in the same codon leading to a different amino acid change at this position (p.Ser1028Arg; p.Ser1028Ile) have been classified as Likely Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (PM5_Supporting). Co-segregation data shows that this variant segregated with FAP in 6 meiosis in one family (PP1_Moderate; Ambry internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, due to insufficient evidence, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: PS4_Supporting, PM5_Supporting, PP1_Moderate and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 15, 2023	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: 428186). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1028 of the APC protein (p.Ser1028Asn). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The p.S1028N pathogenic mutation (also known as c.3083G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 3083. The serine at codon 1028 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Personal communication). This alteration was shown to segregate with disease in one family (Ambry internal data). A nearby amino acid, APC p.N1026, likely interacts directly with APC p.S1028. A missense alteration at the nearby amino acid, APC p.N1026S, which was also shown to segregate with AFAP, is impaired in its ability to bind to β-Catenin and, thus, impaired in reducing β-Catenin signaling (Menéndez M et al. Gastroenterology. 2008 Jan;134:56-64; Kohler EM et al. Hum. Mol. Genet. 2008 Jul;17:1978-87). Internal structural analysis shows that this variant (p.S1028N) lies on the protein interface that is indicated to be important for β-Catenin binding (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.90, 0.66
MutPred		0.72		.;Loss of phosphorylation at S1028 (P = 0.1007);Loss of phosphorylation at S1028 (P = 0.1007);Loss of phosphorylation at S1028 (P = 0.1007);
MVP		0.91
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.77

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: rs1114167617; hg19: chr5-112174374;