rs144655979

chr5-112839806-C-Achr5-112839806-C-Gchr5-112839806-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000038.6(APC):c.4212C>A(p.Ser1404=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1404S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.06

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-112839806-C-A is Benign according to our data. Variant chr5-112839806-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 135700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839806-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4212C>A	p.Ser1404=	synonymous_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4212C>A	p.Ser1404=	synonymous_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000797 AC: 20 AN: 251010 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135628

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

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: 0.000141

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461860 Hom.: 1 Cov.: 33 AF XY: 0.000131 AC XY: 95 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74292

Gnomad4 AFR AF: 0.0000242

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: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000982

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	APC: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2017	Variant summary: The APC c.4212C>A (p.Ser1404Ser) variant causes a synonymous change involving a non-conserved nucleotide, 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 11/121300 (1/11025), which exceeds the estimated maximal expected allele frequency for a pathogenic APC variant of 1/14005, therefore, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 25, 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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 15, 2016	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2019	- -

Familial adenomatous polyposis 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 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. -

Classic or attenuated familial adenomatous polyposis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	0.068
Dann	Benign	0.75

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: rs144655979; hg19: chr5-112175503; COSMIC: COSV104567851; COSMIC: COSV104567851;