chr5-112767263-C-T

Variant names:

• chr5-112767263-C-T
• rs139196838
• NM_000038.6:c.295C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP1 BP2 BP5 BS1 BS2

This summary comes from the ClinGen Evidence Repository: The c.295C>T variant in APC is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid position 99 (p.Arg99Trp). 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). The highest population minor allele frequency of the variant c.295C>T in gnomAD v2.1.1 (non-cancer) is 0.0007355 (95/129170 alleles) in the European (non-Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001%) for BS1 (BS1). This variant has been observed in heterozygous state in more than 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae and Ambry Genetics internal data). It has also been observed once in a homozygous state (Ambry Genetics internal data). This variant has been observed 4 times with other APC variants deemed (likely) pathogenic by the HCCP VCEP in individuals with FAP (BP2; PMIDs 23159591, 25604157, Bonn internal data). Finally, this variant has been observed in 6 patients with an alternate molecular basis for disease (BP5; Leiden University Medical Center internal data). 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, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA007948/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: APC NM_001354906.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:7 B:16
• Conservation: PhyloP100: 1.59

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 Benign. Variant got -11 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.295C>T	p.Arg99Trp	missense_variant	Exon 4 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.295C>T	p.Arg99Trp	missense_variant	Exon 4 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251458 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135906

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000765

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000815 AC: 1191 AN: 1461846 Hom.: 1 Cov.: 31 AF XY: 0.000822 AC XY: 598 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74280

Gnomad4 AFR AF: 0.000459

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000599 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000872

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Uncertain:7 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2 Benign:4

Feb 18, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.295C>T variant in APC is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid position 99 (p.Arg99Trp). 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). The highest population minor allele frequency of the variant c.295C>T in gnomAD v2.1.1 (non-cancer) is 0.0007355 (95/129170 alleles) in the European (non-Finnish) population, which is higher than the HCCP VCEP threshold (0.001%) for BS1 (BS1). This variant has been observed in heterozygous state in more than 1000 healthy unrelated adult individuals worth more than 10 healthy individual points in total (BS2; Invitae and Ambry Genetics internal data). It has also been observed once in a homozygous state (Ambry Genetics internal data). This variant has been observed 4 times with other APC variants deemed (likely) pathogenic by the HCCP VCEP in individuals with FAP (BP2; PMIDs 23159591, 25604157, Bonn internal data). Finally, this variant has been observed in 6 patients with an alternate molecular basis for disease (BP5; Leiden University Medical Center internal data). 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, BP1, BP2 (VCEP specifications version 1; date of approval 12/12/2022). -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Uncertain:2 Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Seen in one 38 year old with no polyps. Penetrance of APC is close to 100%. MaxMAF is 0.064% (higher than frequency of FAP). -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 29, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:3

Apr 18, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The APC c.295C>T variant affects a non-conserved nucleotide, resulting in an amino acid change from a large size and basic Arg to a large size and aromatic Trp. 5/5 in-silico tools predict a damaging outcome for this variant, but these predictions have not been verified with functional studies. This variant was found in 48/121376 control chromosomes at a frequency of 0.0003955, which is about 7 times the maximal expected frequency of a pathogenic APC allele (0.0000602), suggesting this variant is benign. Furthermore, the variant was shown not to co-segregate with disease in one family (Dobbie_Eur J Cancer_1994), and the variant was reported to co-occur with deleterious APC variants, p.S1222X and large deletion of exon 15, respectively (Kerr_JMD_2013). In addition, several clinical laboratories classified this variant as benign/likely benign. Taken together, this variant was classified as benign. -

May 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: BP1, BP2, BS3:Supporting, BS1 -

Jan 09, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.295C>T, p.Arg99Trp variant (rs139196838) has been reported in patients with attenuated familial adenomatous polyposis (Heinimann 2001, Jelsig 2016, Mindel 2011, Out 2015), but has also been found in trans with another APC pathogenic variant (Kerr 2013). The variant is listed in ClinVar (Variation ID: 135695), and observed in the general population at an overall frequency of 0.04% (115/277190 alleles) in the Genome Aggregation Database. The arginine at residue 99 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Due to the limited information regarding this variant, its clinical significance could not be determined with certainty. References: Heinimann K et al. Nontruncating APC germ-line mutations and mismatch repair deficiency play a minor role in APC mutation-negative polyposis. Cancer Res. 2001; 61(20):7616-22. Jelsig A et al. Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps. Scand J Gastroenterol. 2016; 51(9):1118-25. Kerr S et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013; 15(1):31-43. Minde D et al. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? Mol Cancer. 2011; 10:101. Out A et al. High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations. Fam Cancer. 2015; 14(2):247-57. -

Hereditary cancer-predisposing syndrome Benign:3

Mar 18, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 25, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Colorectal cancer, susceptibility to Uncertain:1

Mar 25, 2016

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APC p.Arg99Trp variant was identified in 7 of 3802 proband chromosomes (frequency: 0.002) from individuals or families with hamartomatous polyposis syndrome and familial adenomatous polyposis (Dobbie 1996, Heinimann 2001, Out 2015, Jelsig 2016, Kerr 2013). The variant was identified in dbSNP (rs139196838) as “with uncertain significance, other allele”, ClinVar (classified as uncertain significance by Counsyl, Mayo Clinic, Quest Diagnostics and 4 other submitters, likely benign by Color, Ambry Genetics, GeneDx and Sinai Health System and benign by Invitae and Integrated Genetics), LOVD 3.0 (observed 11x) and UMD-LSDB. The variant was identified in control databases in 113 of 282,846 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 95 of 129,170 chromosomes (freq: 0.0007), African in 9 of 24,968 chromosomes (freq: 0.0004), Other in 2 of 7224 chromosomes (freq: 0.0003), Finnish in 3 of 25,118 chromosomes (freq: 0.0001), Latino in 3 of 35,436 chromosomes (freq: 0.00009), East Asian in 1 of 19,944 chromosomes (freq: 0.00005), while the variant was not observed in the Ashkenazi Jewish and South Asian populations. The variant was identified in individuals in trans with pathogenic APC variants (p.Ser1222* and exon 15 deletion) (Kerr 2013). The p.Arg99 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Classic or attenuated familial adenomatous polyposis Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

APC-related disorder Benign:1

Jun 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;D;D;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.69	.;.;N;N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;N;N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		1.0	.;.;D;D;.
Vest4		0.70, 0.75
MVP		0.94
ClinPred		0.13	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.30

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

Other links and lift over

dbSNP: rs139196838; hg19: chr5-112102960; COSMIC: COSV57367627; COSMIC: COSV57367627;