rs727504420

Positions:

• chr5-112839847-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000038.6(APC):​c.4255del​(p.Ser1419AlafsTer54) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I1418I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.570

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.

• 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 345 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112839847-TA-T is Pathogenic according to our data. Variant chr5-112839847-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177952.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4255del	p.Ser1419AlafsTer54	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4255del	p.Ser1419AlafsTer54	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial multiple polyposis syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2011

The Ser1419fsx54 variant has not been previously reported in the literature or b een identified by our laboratory. However, an adjacent nucleotide variant, 4256d elG, resulting in a similar amino acid change, Ser1419fsX54, was identified in t umor tissue from an individual with colorectal carcinoma but not FAP (Lovig 2002 ; COSMIC). The Ser1419fsx54 variant is predicted to cause a frameshift, which al ters the protein's amino acid sequence beginning at codon 1419 and leads to a pr emature stop codon 54 amino acids downstream. From this DNA sequencing test, we cannot determine the effect this nucleotide change will have on the protein prod uced. It is possible that a truncated protein is generated. Alternatively, no pr otein would be produced from this allele if nonsense-mediated decay occurs, as p remature stop codons frequently result in degradation of the mRNA. Frameshift va riants in APC are commonly observed to be pathogenic, and loss of function of AP C is an established mechanism of disease in FAP (Human Mutation Gene Database, H GMD). Therefore, this variant is likely to be 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: rs727504420; hg19: chr5-112175544;