rs140868933

Positions:

• chr5-112843662-G-A
• chr5-112843662-G-C
• chr5-112843662-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000038.6(APC):​c.8068G>A​(p.Ala2690Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,613,912 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2690P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 4.11

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055845976).
• BP6: Variant 5-112843662-G-A is Benign according to our data. Variant chr5-112843662-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112843662-G-A is described in Lovd as [Benign]. Variant chr5-112843662-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.8068G>A	p.Ala2690Thr	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.8068G>A	p.Ala2690Thr	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152082 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00238 AC: 599 AN: 251260 Hom.: 3 AF XY: 0.00250 AC XY: 339 AN XY: 135798

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00137 AC: 2009 AN: 1461712 Hom.: 7 Cov.: 34 AF XY: 0.00142 AC XY: 1032 AN XY: 727164

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.000991

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152200 Hom.: 2 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74426

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0131

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000987 Hom.: 1

Bravo AF: 0.000525

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00256 AC: 311

EpiCase AF: 0.000818

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.5% (102/6614) Finnish; ClinVar: 3 B, 1 VUS -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 02, 2017	- -
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	Genetic Services Laboratory, University of Chicago	Jul 12, 2018	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 07, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 30, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 21, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 05, 2018	- -

Familial adenomatous polyposis 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Pathway Genomics	Nov 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 12, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

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.Ala2690Thr variant was not identified in the literature. The variant was identified in dbSNP (rs140868933) as “with other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics, GeneDx, Color and 4 other submitters and likely benign by True Health Diagnostics and 1 other submitter), LOVD 3.0 (observed 6x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 663 of 282,646 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 354 of 25,120 chromosomes (freq: 0.01), Other in 18 of 7220 chromosomes (freq: 0.002), European in 264 of 128,976 chromosomes (freq: 0.002), South Asian in 19 of 30,616 chromosomes (freq: 0.0006), Latino in 6 of 35,434 chromosomes (freq: 0.0002), African in 2 of 24,962 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, and East Asian populations. The p.Ala2690Thr residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

APC: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.077
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.30	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.24	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0010	B;B
Vest4		0.097
MVP		0.60
ClinPred		0.015	T
GERP RS		5.9
Varity_R		0.067
gMVP		0.25

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: rs140868933; hg19: chr5-112179359; COSMIC: COSV104567619; COSMIC: COSV104567619;