rs67622085

Positions:

• chr5-112839920-T-A
• chr5-112839920-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000038.6(APC):​c.4326T>A​(p.Pro1442=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,842 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1442P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (103 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.824

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-112839920-T-A is Benign according to our data. Variant chr5-112839920-T-A is described in ClinVar as [Benign]. Clinvar id is 132705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839920-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.824 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00736 (1119/151984) while in subpopulation NFE AF= 0.0114 (775/67952). AF 95% confidence interval is 0.0107. There are 8 homozygotes in gnomad4. There are 502 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4326T>A	p.Pro1442=	synonymous_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4326T>A	p.Pro1442=	synonymous_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 1119 AN: 151866 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00682

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00578

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00719 AC: 1807 AN: 251150 Hom.: 8 AF XY: 0.00718 AC XY: 974 AN XY: 135734

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.0113 AC: 16540 AN: 1461858 Hom.: 103 Cov.: 33 AF XY: 0.0111 AC XY: 8044 AN XY: 727224

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.00696

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.00965

GnomAD4 genome AF: 0.00736 AC: 1119 AN: 151984 Hom.: 8 Cov.: 32 AF XY: 0.00676 AC XY: 502 AN XY: 74280

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.00681

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00578

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00686 Hom.: 1

Bravo AF: 0.00788

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0115

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 22, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2016	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 28, 2017	- -

Familial adenomatous polyposis 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 26, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	APC: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2022

- -

APC-Associated Polyposis Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The Pro1442Pro variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs67622085) from a clinical source with an average heterozygosity and standard error of 0.018 +/- 0.093, and a global minor allele frequency (MAF) of 0.006 (1000 Genomes). It has not been previously identified by our laboratory among the 973 individuals who have undergone APC testing, but has been reported in the literature in 5/528 proband chromosomes (frequency 0.009) from individuals with colorectal cancer and sporadic ependymomas. It was found at higher frequencies in the 4/282 control chromosomes (frequency 0.014), increasing the likelihood that this is a benign variant (Onilude_2006_16843107, Worm_2004_15133491, Zhou_2004_15122587). In summary, based on the above information, the p.Pro1442ro variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.1
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs67622085; hg19: chr5-112175617; COSMIC: COSV57332204; COSMIC: COSV57332204;