5-112840513-G-T

Position:

• chr5-112840513-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000038.6(APC):​c.4919G>T​(p.Arg1640Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1640W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.43

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.4919G>T	p.Arg1640Leu	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.4919G>T	p.Arg1640Leu	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2021

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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 825288). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 1640 of the APC protein (p.Arg1640Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2018

The p.R1640L variant (also known as c.4919G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 4919. The arginine at codon 1640 is replaced by leucine, an amino acid with dissimilar properties. A different alteration at this position, p.R1640Q, was reported in an individual with early onset colorectal cancer; however, it was also reported in a cohort of 681 ancestrally diverse, healthy subjects (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). In addition, p.R1640W (designated as 1841Arg>Trp) was reported in a familial adenomatous polyposis (FAP) kindred and segregated with disease in multiple affected family members; however, the presence of a gross deletion in APC was not ruled out in these samples (Stella A et al. Hum Mol Genet. 1994 Sep;3(9):1687-8). More recently, p.R1640W was detected in conjunction with a second missense variant in a FAP patient, but no familial testing to determine segregation with disease was performed (Scott R et al. Hered Cancer Clin Pract. 2004;2(2):81-91). This amino acid position is highly conserved in available vertebrate species. In addition, p.R1640L is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.88	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.61	T;T
Sift4G	Benign	0.67	T;T
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.66		Gain of stability (P = 0.0212);Gain of stability (P = 0.0212);
MVP		0.96
ClinPred		0.56	D
GERP RS		6.2
Varity_R		0.25
gMVP		0.63

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: rs529480958; hg19: chr5-112176210; COSMIC: COSV57381733; COSMIC: COSV57381733;