rs1060503292

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000038.6(APC):​c.6553A>G​(p.Ser2185Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. S2185N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

APC
NM_000038.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.41
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.15346304).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APCNM_000038.6 linkuse as main transcriptc.6553A>G p.Ser2185Gly missense_variant 16/16 ENST00000257430.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.6553A>G p.Ser2185Gly missense_variant 16/165 NM_000038.6 P1P25054-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 08, 2023This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2185 of the APC protein (p.Ser2185Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gallbladder and pancreatic cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 411410). 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. 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. -
Malignant tumor of ascending colon Uncertain:1
Uncertain significance, no assertion criteria providedclinical testing3DMed Clinical Laboratory IncDec 14, 2017- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 03, 2019The p.S2185G variant (also known as c.6553A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 6553. The serine at codon 2185 is replaced by glycine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. This alteration was reported in a cohort of Asian patients with multiple primary cancer diagnoses undergoing multigene panel testing for hereditary cancer susceptibility (Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660). 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
0.074
BayesDel_addAF
Benign
-0.044
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
19
DANN
Benign
0.92
DEOGEN2
Uncertain
0.43
T;T
Eigen
Benign
-0.030
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
0.34
N;N
MutationTaster
Benign
0.97
N;N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.71
N;N
REVEL
Benign
0.23
Sift
Benign
0.10
T;T
Sift4G
Benign
0.31
T;T
Polyphen
0.0
B;B
Vest4
0.20
MutPred
0.17
Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);
MVP
0.76
ClinPred
0.36
T
GERP RS
6.0
Varity_R
0.077
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060503292; hg19: chr5-112177844; API