chr5-112843130-T-G

Position:

• chr5-112843130-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000038.6(APC):​c.7536T>G​(p.Ser2512Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.198

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16652814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.7536T>G	p.Ser2512Arg	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.7536T>G	p.Ser2512Arg	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 2512 of the APC protein (p.Ser2512Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 664699). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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. -

Classic or attenuated familial adenomatous polyposis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 16, 2023

This missense variant replaces serine with arginine at codon 2512 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The p.S2512R variant (also known as c.7536T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 7536. The serine at codon 2512 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.76	N;N
MutationTaster	Benign	0.56	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.38	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.39	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.38	B;B
Vest4		0.34
MutPred		0.45		Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);
MVP		0.79
ClinPred		0.89	D
GERP RS		1.1
Varity_R		0.059
gMVP		0.48

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: rs587780604; hg19: chr5-112178827; COSMIC: COSV57377169; COSMIC: COSV57377169;