5-112839970-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000038.6(APC):c.4376C>G(p.Thr1459Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1459A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -0.302

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 15 uncertain in NM_000038.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.04275018).
• BP6: Variant 5-112839970-C-G is Benign according to our data. Variant chr5-112839970-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 230474.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4376C>G	p.Thr1459Ser	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4376C>G	p.Thr1459Ser	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251194 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 15, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 25, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 22, 2022

To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000008 (2/251194 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Classic or attenuated familial adenomatous polyposis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.033
Dann	Benign	0.55
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.22	N;N
REVEL	Benign	0.20
Sift	Benign	0.81	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0	B;B
Vest4		0.047
MutPred		0.17		Loss of glycosylation at T1459 (P = 0.0312);Loss of glycosylation at T1459 (P = 0.0312);
MVP		0.60
ClinPred		0.021	T
GERP RS		-1.0
Varity_R		0.015
gMVP		0.29

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: rs756048549; hg19: chr5-112175667;