5-112840377-G-T

Position:

• chr5-112840377-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000038.6(APC):​c.4783G>T​(p.Ala1595Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,876 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. A1595P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.40

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 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000038.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08619887).
• BP6: Variant 5-112840377-G-T is Benign according to our data. Variant chr5-112840377-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411531.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4783G>T	p.Ala1595Ser	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4783G>T	p.Ala1595Ser	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251196 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

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: 0.00000274 AC: 4 AN: 1461876 Hom.: 0 Cov.: 65 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2021	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. -

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2023

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. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1595 of the APC protein (p.Ala1595Ser). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 411531). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.19
Sift	Benign	0.70	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.079
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.69
ClinPred		0.053	T
GERP RS		4.2
Varity_R		0.076
gMVP		0.16

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: rs749782426; hg19: chr5-112176074;