5-112840632-C-G

Position:

• chr5-112840632-C-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.5038C>G​(p.Gln1680Glu) 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 1,461,600 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 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: 0.865

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07652658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.5038C>G	p.Gln1680Glu	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.5038C>G	p.Gln1680Glu	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+11660C>G		intron_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250054 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461600 Hom.: 0 Cov.: 63 AF XY: 0.00 AC XY: 0 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Gln1680Glu variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs754122018) as "With Pathogenic allele" however this entry also refers to the T allele at this loci which creates a termination codon. The variant was identified in control databases in 1 of 244862 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 1 of 33510 chromosomes (freq: 0.00003), but not in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln1680 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2022	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. 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. ClinVar contains an entry for this variant (Variation ID: 657857). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs754122018, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1680 of the APC protein (p.Gln1680Glu). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2022

The p.Q1680E variant (also known as c.5038C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 5038. The glutamine at codon 1680 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. 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	Benign	0.070
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.21
Sift	Benign	0.65	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.091
MutPred		0.12		Gain of methylation at R1676 (P = 0.1039);Gain of methylation at R1676 (P = 0.1039);
MVP		0.61
ClinPred		0.055	T
GERP RS		5.0
Varity_R		0.076
gMVP		0.14

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: rs754122018; hg19: chr5-112176329;