chr5-112840326-T-G

Position:

chr5-112840326-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. BS3_SupportingBP1PS4

This summary comes from the ClinGen Evidence Repository: The c.4732T>G variant in APC is a missense variant predicted to cause the substitution of cysteine by glycine at amino acid position 1578 (p.Cys1578Gly). This variant has been reported in 21 families with FAP worth 9 phenotype points (PS4, Ambry, GeneDX and Invitae internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.0009780% in the non-Finnish European population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel’s (HCCP VCEP) threshold ≤ 0.0008% for PM2_Supporting (PM2_Supporting not met). A luciferase reporter plasmid transiently transfected into SW480 cells is able to suppress beta-catenin-regulated transcription indicating that this variant does not impact protein function (BS3_Supporting; PMID 18199528). APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). 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: PS4, BS3_Supporting, BP1 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA009712/MONDO:0021056/089

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:6

Conservation

PhyloP100: 7.67

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]

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

BP1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.4732T>G	p.Cys1578Gly	missense_variant	16/16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.4732T>G	p.Cys1578Gly	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.228+11354T>G		intron_variant		3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250924

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000902

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1578 of the APC protein (p.Cys1578Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial adenomatous polyposis (PMID: 18199528; Invitae). ClinVar contains an entry for this variant (Variation ID: 140839). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APC function (PMID: 18199528). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 26, 2023	The c.4732T>G variant in APC is a missense variant predicted to cause the substitution of cysteine by glycine at amino acid position 1578 (p.Cys1578Gly). This variant has been reported in 21 families with FAP worth 9 phenotype points (PS4, Ambry, GeneDX and Invitae internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.0009780% in the non-Finnish European population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel’s (HCCP VCEP) threshold (0.0008%) for PM2_Supporting (PM2_Supporting not met). A luciferase reporter plasmid transiently transfected into SW480 cells is able to suppress beta-catenin-regulated transcription indicating that this variant does not impact protein function (BS3_Supporting; PMID 18199528). APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). 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: PS4, BS3_Supporting, BP1 (VCEP specifications version 1; date of approval: 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2023	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2019	The APC c.4732T>G; p.Cys1578Gly variant (rs138367627) is reported in the literature in an individual affected with multiple colorectal adenomas (Azzopardi 2008). This variant is found on a single chromosome (1/250924 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 1578 is highly conserved across species, located in the SAMP repeats/axin binding domain (Azzopardi 2008), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, in functional assays, the p.Cys1578Gly variant suppressed beta-catenin-regulated transcription to the same extent as wildtype protein (Azzopardi 2008). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Azzopardi D et al. Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. Cancer Res. 2008 Jan 15;68(2):358-63. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 21, 2019	Variant summary: APC c.4732T>G (p.Cys1578Gly) results in a non-conservative amino acid change located in the SAMP repeats/axin binding domain (Azzopardi 2008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250924 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4732T>G has been reported in the literature in one individual affected with colorectal adenomas (Azzopard_2008). The report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Azzopard_2008). Four ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic (2x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2024

Published functional study demonstrates CRT suppression similar to wild type (PMID: 18199528); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21859464, 18199528, 24055113, 28152038, 25637381, 37542411) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The p.C1578G variant (also known as c.4732T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 4732. The cysteine at codon 1578 is replaced by glycine, an amino acid with highly dissimilar properties. This variant has been detected in multiple individuals with colorectal polyposis, and it is located in a conserved SAMP repeat that functions as an axin binding domain (Azzopardi et al. Cancer Res. 2008 Jan;68:358-63; Minde DP et al. Mol. Cancer. 2011 Aug;10:101; Spink KE et al. EMBO J. 2000 May;19:2270–9; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Jan 11, 2024

This missense variant replaces cysteine with glycine at codon 1578 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant retained >80% of wild-type APC inhibitory activity on beta--Catenin as assessed by beta--Catenin-regulated transcription (CRT) assays (PMID: 18199528). This variant has been reported in individuals affected with familial adenomatous polyposis and colorectal adenoma (ClinVar: SCV000172947.9, SCV000260260.11, SCV000293423.12; PMID: 18199528). This variant has been identified in 1/250924 chromosomes 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. -

Colorectal adenoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

.;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.3

D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.91

MVP

1.0

ClinPred

0.99

GERP RS

6.2

Varity_R

0.84

gMVP

0.77

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over