rs1060503261

chr5-112801383-G-Achr5-112801383-G-C

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.834G>A(p.Gln278=) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 5.51

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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-112801383-G-A is Pathogenic according to our data. Variant chr5-112801383-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112801383-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.834G>A	p.Gln278=	splice_region_variant, synonymous_variant	8/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.834G>A	p.Gln278=	splice_region_variant, synonymous_variant	8/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 12, 2019	A different variant affecting this nucleotide (c.834G>C) has been determined to be pathogenic (PMID: 18433509). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individuals and families affected with familial adenomatous polyposis (PMID: 20223039, 23159591, Invitae). ClinVar contains an entry for this variant (Variation ID: 411344). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 278 of the APC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the APC protein. This variant also falls at the last nucleotide of exon 8 of the APC coding sequence, which is part of the consensus splice site for this exon. -
Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Sep 26, 2023	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.834G>A pathogenic mutation (also known as p.Q278Q), located in coding exon 7 of the APC gene, results from a G to A substitution at nucleotide position 834. This nucleotide substitution does not change the protein at codon 278. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This alteration has previously been reported in a family meeting diagnostic criteria for FAP or attenuated FAP (Friedl W et al. Hered Cancer Clin Pract 2005; 3(3):95-114; Kerr SE et al. J Mol Diagn 2013 Jan; 15(1):31-43). In addition, this alteration has been observed in multiple individuals with a personal and/or family history that is consistent with FAP/AFAP (Ambry internal data). A different alteration at the same position (c.834G>C) was previously reported in a family with FAP and was shown to create an alternative cryptic splice donor site 11 bp upstream, resulting in aberrant splicing of coding exon 7 (Kanter-Smoler G et al. BMC Med 2008; 6:10). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site, however, direct evidence is insufficient at this time (Ambry internal data). 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	-0.32
Cadd	Uncertain	26
Dann	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.78		Position offset: -11
DS_DL_spliceai		0.30		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: rs1060503261; hg19: chr5-112137080;