5-112767388-G-C

Position:

chr5-112767388-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. BS2PM2_SupportingBP1BP2

This summary comes from the ClinGen Evidence Repository: The c.420G>C variant in APC is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 140 (p.Glu140Asp). APCis 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 heterozygous state in 67 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data). This variant has also been observed in trans with a variant classified as (likely) pathogenic by the HCCP VCEP in an individual with FAP (BP2; Invitae Internal Data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA008951/MONDO:0021056/089

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APC
NM_000038.6 missense, splice_region

Scores

Splicing: ADA: 0.0001798

Clinical Significance

Likely benign reviewed by expert panel U:8B:3

Conservation

PhyloP100: 0.171

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 Likely_benign. Variant got -5 ACMG points.

PM2

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

BP1

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

BP2

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

BS2

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.420G>C	p.Glu140Asp	missense_variant, splice_region_variant	4/16	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.420G>C	p.Glu140Asp	missense_variant, splice_region_variant	4/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460442

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726684

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 31, 2022	- -
Likely benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 18, 2023	The c.420G>C variant in APC is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 140 (p.Glu140Asp). APCis 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 heterozygous state in 67 healthy unrelated adult individuals worth more than 10 healthy individual points in total (BS2; Ambry Genetics, Invitae, GeneDX internal data). This variant has also been observed in trans with a variant classified as (likely) pathogenic by the HCCP VCEP in an individual with FAP (BP2; Invitae Internal Data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 22, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 24, 2016	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 11, 2022	This missense variant replaces glutamic acid with aspartic acid at codon 140 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2023	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 05, 2023

Variant summary: APC c.420G>C (p.Glu140Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.420G>C has been reported in the literature in at least one individual affected with breast cancer without strong evidence for causality (e.g., Tung_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26976419). Six ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. Four clinical diagnostic laboratories classified the variant as a variant of uncertain significance, while one clinical diagnostic laboratory and one expert panel classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Jul 29, 2024

This missense variant replaces glutamic acid with aspartic acid at codon 140 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). 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

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;D;D;T

Eigen

Benign

-0.079

Eigen_PC

Benign

-0.081

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

D;.;D;D

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Uncertain

0.042

MutationAssessor

Benign

1.1

.;L;L;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.019

D;D;D;D

Polyphen

0.15

.;B;B;.

Vest4

0.76, 0.79

MutPred

0.16

.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.89

ClinPred

0.95

GERP RS

-0.72

Varity_R

0.70

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.28

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