chr5-112841727-TC-T

Variant names:

• chr5-112841727-TC-T
• rs1554087239
• NM_000038.6:c.6135delC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000038.6(APC):​c.6135delC​(p.Ala2046GlnfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.50

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112841727-TC-T is Pathogenic according to our data. Variant chr5-112841727-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 433673.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-112841727-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.6135delC	p.Ala2046GlnfsTer27	frameshift_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.6135delC	p.Ala2046GlnfsTer27	frameshift_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+12757delC		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Carcinoma of colon Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APC p.Ala2046GlnfsX27 variant was not identified in dbSNP, Clinvitae database, COSMIC, Zhejiang Colon Cancer Database, ClinVar database, GeneInsight - COGR database, UMD, NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The variant was identified only in InSiGHT Colon Cancer Gene Variant Database (LOVD) and classified as pathogenic. The c.6135delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2046 and leads to a premature stop codon 27 codons downstream. This alteration is then predicted to result in 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 addition, one genotype-phenotype correlations study (Soravia 1998) identify the variant in the patient with very mild colonic phenotype, <40 polips, no CRC and rectal-polyp sparing. This variant of FAP has been termed “hereditary desmoid disease” and had been classified as “familial infiltrative fibromatosis”. Therefore it’s considered as an attenuated adenomatous polyposis coli (AAPC) variant with predominance of desmoid tumors. 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

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: rs1554087239; hg19: chr5-112177424;