rs1060503318
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000038.6(APC):c.1958G>A(p.Arg653Lys) 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. 3/3 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. R653G) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
APC
NM_000038.6 missense, splice_region
NM_000038.6 missense, splice_region
Scores
9
9
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.60
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a repeat ARM 5 (size 44) in uniprot entity APC_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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 chr5-112835164-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894
PP5
Variant 5-112835165-G-A is Pathogenic according to our data. Variant chr5-112835165-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 428128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112835165-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.1958G>A | p.Arg653Lys | missense_variant, splice_region_variant | 15/16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
| ENSG00000258864 | ENST00000520401.1 | n.228+6193G>A | intron_variant | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC p.Arg653Lys variant was identified in 7 of 15446 proband chromosomes (frequency: 0.0005) from individuals or families with familial colorectal adenomas and colorectal cancer and was not identified in 1938 control chromosomes from healthy individuals (Azzopardi 2008, Inra 2015, Lagarde 2010). The variant was also identified in ClinVar (classified as pathogenic by Invitae; as likely pathogenic by Ambry Genetics), Cosmic (4x in large intestine), LOVD 3.0 (1x as affects function), and in UMD-LSDB (8x causal) databases. The variant was not identified in dbSNP, COGR, MutDB, or Zhejiang University databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Arg653 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Arg653Lys variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. 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 addition, in vitro analysis by RT-PCR and ex vivo analysis by Splicing reporter minigene pCAS, showed major loss of exon 14 during splicing (Grandval 2014). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Familial adenomatous polyposis 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 05, 2023 | This sequence change affects codon 653 of the APC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial adenomatous polyposis and colorectal cancer (PMID: 18199528, 20685668, 24599579, 25590978). ClinVar contains an entry for this variant (Variation ID: 428128). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 15 (also known as exon 14) and introduces a new termination codon (PMID: 20685668, 24599579). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 08, 2020 | This variant has been reported in in individuals with colorectal adenomas in the published literature (PMIDs: 18199528 (2008) and 20685668 (2010)). This variant also causes exon 15 skipping (PMID: 20685668 (2010)). Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper APC mRNA splicing . Therefore, the variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2022 | The c.1958G>A pathogenic variant (also known as p.R653K) is located in coding exon 14 of the APC gene. This variant results from a G to A substitution at nucleotide position 1958. The amino acid change results in arginine to lysine at codon 653, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 14 which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration, as well as a close match alteration, c.1958G>T, has been detected in multiple patients with FAP (Azzopardi D et al. Cancer Res. 2008 Jan 15;68(2):358-63; Minde DP et al. Mol Cancer. 2011 Aug 22;10:101; ). RNA studies have demonstrated that this alteration, as well as a close match alteration, c.1958G>T, results in abnormal splicing in the set of samples tested (Ambry internal data; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D;D;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;M;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;.
Sift4G
Uncertain
D;D;D;D;D
Polyphen
1.0
.;D;D;.;.
Vest4
0.88, 0.67
MutPred
0.80
.;Gain of ubiquitination at R653 (P = 0.0198);Gain of ubiquitination at R653 (P = 0.0198);Gain of ubiquitination at R653 (P = 0.0198);.;
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at