5-112827247-G-T

Variant names:

• chr5-112827247-G-T
• rs879254090
• NM_000038.6:c.1548G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000038.6(APC):​c.1548G>T​(p.Lys516Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. K516K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: APC NM_000038.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95
• Publications: 0 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 39 uncertain in NM_000038.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1548G>T	p.Lys516Asn	missense_variant, splice_region_variant	Exon 12 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1548G>T	p.Lys516Asn	missense_variant, splice_region_variant	Exon 12 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.33G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 8	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;D;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;.;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.8	.;L;L;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.93, 0.89
MutPred		0.89		.;Loss of ubiquitination at K516 (P = 0.0161);Loss of ubiquitination at K516 (P = 0.0161);Loss of ubiquitination at K516 (P = 0.0161);.;
MVP		0.82
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.84
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: 38
DS_DL_spliceai		0.73		Position offset: 0

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

Other links and lift over

dbSNP: rs879254090; hg19: chr5-112162944;