rs1114167580

Positions:

• chr5-112835164-A-C
• chr5-112835164-A-G
• chr5-112835164-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000038.6(APC):​c.1957A>C​(p.Arg653=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R653R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.95

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 5-112835164-A-C is Pathogenic according to our data. Variant chr5-112835164-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 482311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112835164-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.1957A>C	p.Arg653=	splice_region_variant, synonymous_variant	15/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1957A>C	p.Arg653=	splice_region_variant, synonymous_variant	15/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 03, 2023

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2016

The c.1957A>C pathogenic mutation (also known as p.R653R), located in coding exon 14, results from an A to C substitution at nucleotide position 1957 of the APC gene. This nucleotide substitution does not change the arginine at codon 653. However, this change occurs two base pairs from the end of coding exon 14. This alteration has been in several unrelated familial adenomatous polyposis (FAP) families (Aretz S, et al. Hum. Mutat. 2004 Nov; 24(5):370-80; Friedl W, et al. Hered Cancer Clin Pract 2005 ; 3(3):95-114; Ambry Internal Data). Analysis of mRNA has demonstrated that this alteration causes aberrant splicing resulting in exon 14 skipping (Aretz S, Hum. Mutat. 2004 Nov; 24(5):370-80). In addition, different nucleotide substitution at the same position (c.1957A>G) has also been identified in individuals with FAP and shown to result in similar exon 14 skipping. Based on the available evidence, c.1957A>C is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1114167580; hg19: chr5-112170861;