5-112839993-C-T

Position:

chr5-112839993-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BS2BS3_SupportingBP1BP5BS1

This summary comes from the ClinGen Evidence Repository: The c.4399C>T variant in APC is a missense variant predicted to cause the substitution of Proline by Serine at amino acid position 1467 (p.Pro1467Ser). 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 a heterozygous state in 75 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae and GeneDX internal data). In addition, it has also been observed in 1 patient with an alternate molecular basis for disease – a pathogenic MSH6 germline variant (BP5; Melbourne Internal data). Functional study of β-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as the wild type (BS3_Supporting; PMID:18199528). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0048% in European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BS3_Supporting, BP1 and BP5 (VCEP Specification version 1, date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA038968/MONDO:0021056/089

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

7

12

Clinical Significance

Benign reviewed by expert panel U:8B:2

Conservation

PhyloP100: 3.33

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP1

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

BP5

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

BS1

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

BS2

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.4399C>T	p.Pro1467Ser	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 linkuse as main transcript	c.4399C>T	p.Pro1467Ser	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.0000239

AC:

6

AN:

251166

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

72

AN:

1461880

Hom.:

0

Cov.:

34

AF XY:

0.0000358

AC XY:

26

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000621

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

32

Alfa

AF:

0.0000533

Hom.:

0

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:8Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 14, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 26, 2023	The c.4399C>T variant in APC is a missense variant predicted to cause the substitution of Proline by Serine at amino acid position 1467 (p.Pro1467Ser). 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 a heterozygous state in 75 healthy unrelated adult individuals worth more than 10 healthy individual points in total (BS2; Ambry Genetics, Invitae and GeneDX internal data). In addition, it has also been observed in 1 patient with an alternate molecular basis for disease – a pathogenic MSH6 germline variant (BP5; Melbourne Internal data). Functional study of beta-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as the wild type (BS3_Supporting; PMID: 18199528). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0048% in European (non-Finnish) population, which is higher than the HCCP VCEP threshold (0.001%) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BS3_Supporting, BP1 and BP5 (VCEP Specification version 1, date of approval: 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1467 of the APC protein (p.Pro1467Ser). This variant is present in population databases (rs749142480, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 18199528, 21859464). ClinVar contains an entry for this variant (Variation ID: 411419). 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	Counsyl	Apr 10, 2017	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 25, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This missense variant replaces proline with serine at codon 1467 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant retained >80% of wild-type activity via catenin-regulated transcription assay (PMID: 18199528). This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 6/251166 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 11, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2022

Observed in at least one individual with multiple colon polyps (Azzopardi 2008); Published functional study demonstrated p.P1467S suppresses beta-catenin-regulated transcription similar to wild-type (Azzopardi 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21859464, 18199528) -

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

Oct 23, 2023

This missense variant replaces proline with serine at codon 1467 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant retained >80% of wild-type activity via catenin-regulated transcription assay (PMID: 18199528). This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 6/251166 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Uncertain

0.11

D

BayesDel_noAF

Uncertain

0.10

CADD

Benign

21

DANN

Benign

0.85

DEOGEN2

Uncertain

0.48

T;T

Eigen

Benign

0.059

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.87

D

LIST_S2

Uncertain

0.87

.;D

M_CAP

Benign

0.054

D

MetaRNN

Benign

0.37

T;T

MetaSVM

Uncertain

-0.12

T

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Benign

0.38

T

PROVEAN

Benign

-0.43

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.23

T;T

Sift4G

Benign

0.66

T;T

Polyphen

0.44

B;B

Vest4

0.69

MutPred

0.72

Loss of helix (P = 0.0076);Loss of helix (P = 0.0076);

MVP

0.98

ClinPred

0.098

T

GERP RS

5.3

Varity_R

0.051

gMVP

0.68

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.

Other links and lift over

dbSNP: rs749142480; hg19: chr5-112175690;