rs1554074763

Variant names:

• chr5-112792486-T-A
• NM_000038.6:c.686T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112792486-T-A
• chr5-112792486-T-C
• chr5-112792486-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000038.6(APC):​c.686T>A​(p.Leu229His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a coiled_coil_region (size 121) in uniprot entity APC_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_000038.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.686T>A	p.Leu229His	missense_variant	Exon 7 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.686T>A	p.Leu229His	missense_variant	Exon 7 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L229H variant (also known as c.686T>A), located in coding exon 6 of the APC gene, results from a T to A substitution at nucleotide position 686. The leucine at codon 229 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D;D;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.78	P;P;.
Vest4		0.70
MutPred		0.31		Loss of stability (P = 0.0304);Loss of stability (P = 0.0304);Loss of stability (P = 0.0304);
MVP		0.95
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-112128183;