5-112828915-G-A

Position:

• chr5-112828915-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000038.6(APC):​c.1686G>A​(p.Thr562=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,794 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T562T) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.847

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-112828915-G-A is Benign according to our data. Variant chr5-112828915-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 183784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.847 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.1686G>A	p.Thr562=	synonymous_variant	14/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1686G>A	p.Thr562=	synonymous_variant	14/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251302 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135808

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727116

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Benign:3

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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 09, 2016	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	APC: BP4, BP7 -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 29, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 20, 2015	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2020	- -

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

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.7
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs770256026; hg19: chr5-112164612;