5-112775629-G-T

Position:

• chr5-112775629-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000038.6(APC):​c.423G>T​(p.Arg141Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,425,464 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.28

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 16 ACMG points.

• PM1: In a helix (size 37) in uniprot entity APC_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000038.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-112775629-G-T is Pathogenic according to our data. Variant chr5-112775629-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 216017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112775629-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.423G>T	p.Arg141Ser	missense_variant, splice_region_variant	5/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.423G>T	p.Arg141Ser	missense_variant, splice_region_variant	5/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425464 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 710044

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: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2021	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 4, which introduces a premature termination codon (PMID: 15459959). The resulting mRNA is expected to undergo nonsense-mediated decay. 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"). ClinVar contains an entry for this variant (Variation ID: 216017). This variant has been observed in individuals with features of familial adenomatous polyposis (PMID: 15459959, 17410430). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 141 of the APC protein (p.Arg141Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 26, 2023	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15459959]. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Arg141Ser variant was identified in 2 of 1834 proband chromosomes (frequency: 0.001) from individuals or families with Attenuated FAP (Aretz 2004). The variant was also identified the COSMIC database, InSiGHT Colon Cancer Gene Variant Database (4x as a splice mutation), and UMD (20x as a causal variant). In addition, functional analysis of the p.Arg141Ser variant has shown complete skipping of Exon 4 due to aberrant splicing (Aretz 2004, Kaufmann 2009). This variant was not identified in control databases: 1000 Genomes Project, Exome Variant Server project or the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015). A case study of a patient with the p.Arg141Ser variant and subsequent testing of her family has further confirmed an AFAP phenotype with this variant (Murphy 2007). The p.Arg141Ser variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D;D;T
Eigen	Benign	0.045
Eigen_PC	Benign	-0.0060
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.2	.;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.89, 0.89
MutPred		0.32		.;Gain of phosphorylation at R141 (P = 0.0196);Gain of phosphorylation at R141 (P = 0.0196);Gain of phosphorylation at R141 (P = 0.0196);
MVP		0.97
ClinPred		1.0	D
GERP RS		0.48
Varity_R		0.93
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.71		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224458; hg19: chr5-112111326; COSMIC: COSV57373596; COSMIC: COSV57373596;