rs116020626

chr5-112775656-A-Gchr5-112775656-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000038.6(APC):c.450A>G(p.Lys150=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000231 in 1,608,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:16
• Conservation: PhyloP100: 3.82

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-112775656-A-G is Benign according to our data. Variant chr5-112775656-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181782.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=5, Uncertain_significance=2}. Variant chr5-112775656-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.450A>G	p.Lys150=	synonymous_variant	5/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.450A>G	p.Lys150=	synonymous_variant	5/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000157 AC: 39 AN: 247832 Hom.: 0 AF XY: 0.000120 AC XY: 16 AN XY: 133758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000311

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000241 AC: 351 AN: 1456126 Hom.: 0 Cov.: 29 AF XY: 0.000239 AC XY: 173 AN XY: 724136

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000677

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000592

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000297

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74442

Gnomad4 AFR AF: 0.00

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: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000102

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 17, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2014	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 24, 2019	- -

APC-Associated Polyposis Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Lys150Lys variant was identified in 1 of 3082 proband chromosomes (frequency: 0.0003) from individuals or families being evaluated for FAP (Kerr 2013). The variant was also identified in dbSNP (ID: rs116020626) “With other allele”, Clinvitae database (with conflicting interpretations), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classification benign by GeneDx, and likely benign by Ambry Genetics and Invitae), and UMD (2x with a “likely neutral” classification, and co-occurring with a pathogenic APC mutation, c.1312+3A>G). This variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004); HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002); NHLBI GO Exome Sequencing Project (ESP) in 4 of 8582 European American alleles, and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 14 of 66536 chromosomes (frequency: 0.0002) from a population of European (Non-Finnish) individuals. The p.Lys150Lys variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 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

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	11
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116020626; hg19: chr5-112111353;