rs879254090

chr5-112827247-G-Achr5-112827247-G-Cchr5-112827247-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000038.6(APC):c.1548G>A(p.Lys516=) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APC NM_000038.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.95

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 12 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 5-112827247-G-A is Pathogenic according to our data. Variant chr5-112827247-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112827247-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1548G>A	p.Lys516=	splice_region_variant, synonymous_variant	12/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1548G>A	p.Lys516=	splice_region_variant, synonymous_variant	12/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 02, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID:19196998, Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change affects codon 516 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 may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with familial adenomatous polyposis (PMID: 19196998). ClinVar contains an entry for this variant (Variation ID: 428116). 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 12 (also known as exon 11) and introduces a premature termination codon (PMID: 19196998; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.1548G nucleotide in the APC gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8990002, 15459959, 17489848, 20685668, 24599579). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.1548G>A pathogenic mutation (also known as p.K516K) is located in coding exon 11 of the APC gene. This mutation results from a G to A substitution at nucleotide position 1548. This nucleotide substitution does not change the lysine at codon 516; however, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. One study identified this mutation in patient who was diagnosed with classic FAP at age 20. Through mRNA analysis, these researchers demonstrated that this alteration leads to both a complete skipping of exon 11 and premature termination in coding exon 12 (Kaufmann A et al. J Mol Diagn. 2009 Mar; 11(2):131-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 38
DS_DL_spliceai		0.46		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254090; hg19: chr5-112162944; COSMIC: COSV57328914;