rs1060503324

Positions:

• chr5-112841355-G-A
• chr5-112841355-G-C
• chr5-112841355-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2_Supporting BP1 BS2_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5761G>A variant in APC is a missense variant predicted to cause the substitution of glycine by serine at amino acid position 1921 (p.Gly1921Ser). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in more than 3 heterozygous individuals with no features of FAP, worth 3 healthy individual points (BS2_Supporting; Ambry Genetics internal data). A luciferase reporter plasmid transiently transfected into SW480 cells shows an inability to suppress beta-catenin-regulated transcription indicating that this variant impacts protein function (PS3_Supporting; PMID 18199528). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2_supporting, BP1, PM2_supporting, and PS3_supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CV411472/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 1.20

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.5761G>A	p.Gly1921Ser	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.5761G>A	p.Gly1921Ser	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:3

Uncertain significance, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 26, 2023	The c.5761G>A variant in APC is a missense variant predicted to cause the substitution of glycine by serine at amino acid position 1921 (p.Gly1921Ser). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in more than 3 heterozygous individuals with no features of FAP, worth 3 healthy individual points (BS2_Supporting; Ambry Genetics internal data). A luciferase reporter plasmid transiently transfected into SW480 cells shows an inability to suppress beta-catenin-regulated transcription indicating that this variant impacts protein function (PS3_Supporting; PMID 18199528). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2_supporting, BP1, PM2_supporting, and PS3_supporting (VCEP specifications version 1; date of approval: 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1921 of the APC protein (p.Gly1921Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple colorectal adenomas (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 411472). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2022	This missense variant replaces glycine with serine at codon 1921 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 been reported in an individual affected with colorectal adenomas (PMID: 18199528). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 18, 2023	The p.G1921S variant (also known as c.5761G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 5761. The glycine at codon 1921 is replaced by serine, an amino acid with similar properties. This alteration was detected in one individual with 11-99 adenomatous colorectal polyps and was not detected in 969 matched healthy controls (Azzopardi D et al. Cancer Res., 2008 Jan;68:358-63). This amino acid position is not 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. -

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

Nov 30, 2023

This missense variant replaces glycine with serine at codon 1921 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 been reported in an individual affected with colorectal adenomas (PMID: 18199528). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.2
DANN	Benign	0.83
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.32	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.33	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0	B;B
Vest4		0.65
MutPred		0.74		Gain of phosphorylation at G1921 (P = 0.0309);Gain of phosphorylation at G1921 (P = 0.0309);
MVP		0.95
ClinPred		0.068	T
GERP RS		2.2
Varity_R		0.019
gMVP		0.23

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: rs1060503324; hg19: chr5-112177052;