5-112839369-A-T

Position:

• chr5-112839369-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000038.6(APC):​c.3775A>T​(p.Ile1259Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1259T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.83

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23078689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.3775A>T	p.Ile1259Leu	missense_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3775A>T	p.Ile1259Leu	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+10397A>T		intron_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 495359). This missense change has been observed in individual(s) with familial adenomatous polyposis (PMID: 30272267). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1259 of the APC protein (p.Ile1259Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 19, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 09, 2016

Variant summary: The APC c.3775A>T (p.Ile1259Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change at Ile1259 to Leu. Ile1259 lies in the DNA repair inhibitory domain; this domain is involved in the regulation of the base excision repair (BER) pathway. APC blocks Pol--directed BER by blocking the dRP-lyase and strand-displacement activities of Pol- (PMID:26334567). Using site-directed mutagenesis, the APC amino acid residues Ile1259 and Tyr1262 have been shown to be important for the interaction and functional activity of Pol-. However, this particular missense change, Ile1259Leu was not studied (I1259A was examined; PMID:17176113). 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). However, this variant has not been evaluated for functional impact by in vivo/vitro studies.This variant was absent in 120528 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.81	L;L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.49	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.97	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.48
MutPred		0.42		Gain of catalytic residue at I1259 (P = 0.0519);Gain of catalytic residue at I1259 (P = 0.0519);Gain of catalytic residue at I1259 (P = 0.0519);
MVP		0.78
ClinPred		0.69	D
GERP RS		6.0
Varity_R		0.22
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs762391822; hg19: chr5-112175066;