5-112835073-C-A

Position:

• chr5-112835073-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.1866C>A​(p.Tyr622Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y622Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.92

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112835073-C-A is Pathogenic according to our data. Variant chr5-112835073-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 233973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112835073-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1866C>A	p.Tyr622Ter	stop_gained	15/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1866C>A	p.Tyr622Ter	stop_gained	15/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 1316610, 28576136, 17963004, 8381580, 20685668, 8187091, 8990002) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 15, 2018	The APC c.1866C>A; p.Tyr622Ter variant (rs876658355) has been observed in individuals and families affected with familial adenomatous polyposis (FAP) ( Miyaki 1994, Miyoshi 1992, Olschwang 1993, van der Luijt 1997). This variant is reported as pathogenic in ClinVar (Variation ID: 233973) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1866C>G; p.Tyr622Ter) has been reported in individuals with FAP and is considered pathogenic (Friedl 2005). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Friedl W et al. Familial Adenomatous Polyposis: Experience from a Study of 1164 Unrelated German Polyposis Patients. Hered Cancer Clin Pract. 2005; 3(3): 95–114. Miyaki M et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011-20. Miyoshi Y et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452-6. Olschwang S et al. Germ-line mutations in the first 14 exons of the adenomatous polyposis coli (APC) gene. Am J Hum Genet. 1993 Feb;52(2):273-9. van der Luijt R et al. Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. Hum Mutat. 1997;9(1):7-16. -
Likely pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 03, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change creates a premature translational stop signal (p.Tyr622*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 1316610, 8187091, 8381580, 8990002, 20685668). ClinVar contains an entry for this variant (Variation ID: 233973). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Tyr622X variant was identified in 5 of 906 proband chromosomes (frequency: 0.006) from individuals or families with Familial adenomatous polyposis (FAP) (Miyoshi_1992_1316610, van der Luijt_1997_8990002, Olschwang_1993_8381580, Enomoto_2000_10768871, Miyaki_1994_8187091). The variant was also identified in HGMD,“InSiGHT Colon Cancer Database, and UMD (11X as an unvalidated variant). The p.Tyr622X variant leads to a premature stop codon at position 622, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The p.Y622* pathogenic mutation (also known as c.1866C>A), located in coding exon 14 of the APC gene, results from a C to A substitution at nucleotide position 1866. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This alteration has been reported in multiple unrelated families diagnosed with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A. 1992 May;89:4452-6; Miyaki M et al. Cancer Res. 1994 Jun;54:3011-20; van der Luijt RB et al. Hum. Mutat. 1997;9:7-16). In one study, this alteration was observed to segregate with disease in a familial FAP kindred (Olschwang S et al. Am. J. Hum. Genet. 1993 Feb;52:273-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98, 0.99
GERP RS		5.1

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: rs876658355; hg19: chr5-112170770; COSMIC: COSV57321735;