5-112819349-G-C

Position:

• chr5-112819349-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000038.6(APC):​c.1312+5G>C variant causes a splice donor 5th base, intron 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: 32)
• Consequence: APC NM_000038.6 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60

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 14 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 5-112819349-G-C is Pathogenic according to our data. Variant chr5-112819349-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112819349-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.1312+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1312+5G>C		splice_donor_5th_base_variant, intron_variant		5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2023

This sequence change falls in intron 10 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 265372). Variants that disrupt 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. This variant disrupts the c.1312+5G nucleotide in the APC gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15459959, 20223039, 22987206). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2016

This variant is denoted APC c.1312+5G>C or IVS10+5G>C and consists of a G>C nucleotide substitution at the +5 position of intron 10 of the APC gene. Multiple in silico models predict this variant to destroy the nearby natural donor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Importantly, two other variants impacting the same nucleotide, APC c.1312+5G>A and c.1312+5G>T, have both been shown in RNA based assays to result in skipping of exon 10, also published as exon 9, resulting in a frameshift and a subsequent premature stop codon (Mihalatos 2005, Varesco 1994). This variant, APC c.1312+5G>C, has been observed in one individual undergoing APC testing at a clinical laboratory (Kerr 2013). APC c.1312+5G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. Based on the currently available information, we consider APC c.1312+5G>C to be a likely pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2020

The c.1312+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 9 in the APC gene. This alteration has been reported in multiple individuals with personal and/or family history consistent with Familial Adenomatous Polyposis (FAP) and /or Attenuated FAP (AFAP) (Ambry internal data, Kerr SE. J Mol Diagn . 2013 Jan;15(1):31-43). A close match alteration, designated as IVS9+5G>A, has been reported in a patient with multiple small polyps in the right colon and was reported as confirmed de novo via familial testing in this patient (Mihalatos M et al. BMC Cancer, 2005 Apr;5:40). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Further, multiple other pathogenic alterations have been reported at this splice junction, including c.1312+3A>G and c.1312+5G>A. 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	-0.29
CADD	Benign	23
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.45		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039507; hg19: chr5-112155046;