5-112841945-A-AGCT

Position:

• chr5-112841945-A-AGCT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM4_Supporting PP3 BP6_Very_Strong BS2

The NM_000038.6(APC):​c.6363_6365dupTGC​(p.Ala2122dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,613,924 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A2122A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (3 hom.)
• Consequence: APC NM_000038.6 disruptive_inframe_insertion
• Clinical Significance: Benign reviewed by expert panel U:4 B:12
• Conservation: PhyloP100: 9.30

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000038.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 5-112841945-A-AGCT is Benign according to our data. Variant chr5-112841945-A-AGCT is described in ClinVar as [Benign]. Clinvar id is 140994.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.6363_6365dupTGC	p.Ala2122dup	disruptive_inframe_insertion	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.6363_6365dupTGC	p.Ala2122dup	disruptive_inframe_insertion	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+12985_228+12987dupTGC		intron_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 250858 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135580

Gnomad AFR exome AF: 0.000246

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: 0.000186

Gnomad NFE exome AF: 0.000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000633 AC: 925 AN: 1461660 Hom.: 3 Cov.: 34 AF XY: 0.000609 AC XY: 443 AN XY: 727144

Gnomad4 AFR exome AF: 0.000179

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: 0.0000562

Gnomad4 NFE exome AF: 0.000808

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74458

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000302

EpiCase AF: 0.000436

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:12

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2 Benign:3

Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 26, 2023	The c.6354TGC[5] or c.6353_6365dup variant in APC is predicted to cause a change in the length of the protein due to an in-frame duplication of one amino acid (p.Ala2122dup). This variant has been observed in >10 heterozygous individuals with no features of FAP, worth > 10 healthy individual points (BS2; Ambry and Invitae internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.05437% in the non-Finnish European population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (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 and BS2 (VCEP specifications version 1; date of approval: 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 30, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Ala2122dup variant was identified in 1 of 342 proband chromosomes (frequency: 0.003) from individuals or families with FAP, but was classified as a VUS by the authors (Out 2015). The variant was also identified in the Clinvitae database (1X with “uncertain significance”), COSMIC (1X found in a lung adenocarcinoma), ClinVar database (1X with uncertain significance, classified by Ambry Genetics), and UMD (1X with an “unclassified variant” classification). The variant was not identified in the general population cohort databases; 1000 Genomes Project, Exome Variant Server project or the Exome Aggregation Consortium (ExAC) database. This variant is an in-frame duplication resulting in the duplication of an Alanine (Ala) residue at codon 2122; the impact of this alteration on APC protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 30, 2016	Variant summary: The APC c.6363_6365dupTGC (p.Ala2121dup) variant involves the insertion of three nucleotides in a 5 alanine repeat region, resulting in an in-frame duplication of single Alanine. One in silico tool predicts a benign outcome for this variant. This variant was found in 36/121200 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0004797 (32/66714). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in affected individuals without strong evidence of causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance/likely benign, all without evidence to independently evaluate. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2021	This variant is associated with the following publications: (PMID: 25980754, 27060149, 27443514, 27978560, 25186627, 25604157, 30671715) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2018	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 05, 2020	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2021	DNA sequence analysis of the APC gene demonstrated a three base pair duplication in exon 16, c.6363_6365dup. This in-frame duplication is predicted to result in the duplication of a alaine residue, p.Ala2122dup, located in an alanine-rich region. This sequence change has been described in the gnomAD database with a frequency of 0.053% in the non-Finnish European subpopulation (dbSNP rs587780602). This duplication has been reported in an individual with colorectal cancer and was considered a variant of uncertain significance (PMID: 27978560). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined. -

APC-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587780602; hg19: chr5-112177642;