rs113782655

chr5-112707795-C-Achr5-112707795-C-Gchr5-112707795-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001407446.1(APC):c.78C>A(p.Ser26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,370,658 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S26I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0084 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (14 hom.)
• Consequence: APC NM_001407446.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 2.81

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00633198).
• BP6: Variant 5-112707795-C-A is Benign according to our data. Variant chr5-112707795-C-A is described in ClinVar as [Benign]. Clinvar id is 133505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00842 (1283/152296) while in subpopulation AFR AF= 0.0296 (1229/41576). AF 95% confidence interval is 0.0282. There are 19 homozygotes in gnomad4. There are 592 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1275 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_001407446.1	c.78C>A	p.Ser26Arg	missense_variant	1/16
APC	NM_001354897.2	c.78C>A	p.Ser26Arg	missense_variant	1/15
APC	NM_001127511.3	c.78C>A	p.Ser26Arg	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000507379.6	c.78C>A	p.Ser26Arg	missense_variant	1/14	2
APC	ENST00000509732.6	c.-19+146C>A		intron_variant		4		P1
APC	ENST00000505350.2	c.78C>A	p.Ser26Arg	missense_variant, NMD_transcript_variant	1/16	3

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1275 AN: 152178 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

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: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00191 AC: 257 AN: 134852 Hom.: 2 AF XY: 0.00155 AC XY: 114 AN XY: 73416

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.00204

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: 0.0000753

Gnomad OTH exome AF: 0.000482

GnomAD4 exome AF: 0.000818 AC: 997 AN: 1218362 Hom.: 14 Cov.: 31 AF XY: 0.000707 AC XY: 421 AN XY: 595224

Gnomad4 AFR exome AF: 0.0297

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000910

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000824

Gnomad4 OTH exome AF: 0.00155

GnomAD4 genome AF: 0.00842 AC: 1283 AN: 152296 Hom.: 19 Cov.: 32 AF XY: 0.00795 AC XY: 592 AN XY: 74480

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00406 Hom.: 0

Bravo AF: 0.00937

ExAC AF: 0.000922 AC: 18

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2013	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	Feb 02, 2017	- -

Familial adenomatous polyposis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Familial multiple polyposis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 13, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 11, 2022

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Feb 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0063	T
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
MutPred		0.22		Loss of glycosylation at S26 (P = 0.0205);
MVP		0.73
ClinPred		0.19	T
GERP RS		4.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113782655; hg19: chr5-112043492;