5-112840487-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.4893T>C(p.Ser1631=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,614,156 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (4 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.509

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=-0.65).
• BP6: Variant 5-112840487-T-C is Benign according to our data. Variant chr5-112840487-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 132688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.509 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00249 (379/152288) while in subpopulation AFR AF= 0.00883 (367/41562). AF 95% confidence interval is 0.00809. There are 5 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 370 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4893T>C	p.Ser1631=	synonymous_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4893T>C	p.Ser1631=	synonymous_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00864

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000589 AC: 148 AN: 251220 Hom.: 0 AF XY: 0.000457 AC XY: 62 AN XY: 135768

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000258 AC: 377 AN: 1461868 Hom.: 4 Cov.: 65 AF XY: 0.000220 AC XY: 160 AN XY: 727236

Gnomad4 AFR exome AF: 0.00935

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152288 Hom.: 5 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74472

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.00294

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2021	- -
Likely 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	Jun 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 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. -

Familial adenomatous polyposis 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 28, 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	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 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. -

APC-Associated Polyposis Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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.Ser1631= variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs35634377) as "With other allele", and in ClinVar (classified as benign by Invitae, GeneDx, Color and three other submitters; and as likely benign by Ambry Genetics and two other submitters). The variant was identified in control databases in 211 of 276950 chromosomes at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 190 of 24022 chromosomes (freq: 0.008, increasing the likelihood this could be a low frequency benign variant), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 16 of 34412 chromosomes (freq: 0.0005), and European in 1 of 126492 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser1631= 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) 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 25, 2016

Variant summary: Variant affects a non-conserved nucleotide and results in a synonymous mutation. Mutation taster predicts disease causing impact while 5/5 in silico tools via Alamut predict no significant effect on normal splicing. It was predominantly observed in the African subcohort of the ExAC project at an allele frequency of 0.538% which exeeds the maximal expected allele frequency of a disease causing APC allele 0.006% indicating a neutral impact. Additionally, clinical diagnostic centers classify variant as Likely Bening/Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	3.8
Dann	Benign	0.66

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: rs35634377; hg19: chr5-112176184; COSMIC: COSV104379199; COSMIC: COSV104379199;