rs2229995

Variant names:

• chr5-112843098-G-A
• rs2229995
• NM_000038.6:c.7504G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112843098-G-A
• chr5-112843098-G-C
• chr5-112843098-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000038.6(APC):​c.7504G>A​(p.Gly2502Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0199 in 1,613,962 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2502D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 32)
  • Exomes 𝑓: 0.020 (372 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: 4.02
• Publications: 55 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006817907).
• BP6: Variant 5-112843098-G-A is Benign according to our data. Variant chr5-112843098-G-A is described in ClinVar as Benign. ClinVar VariationId is 41514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.017 (2589/152258) while in subpopulation SAS AF = 0.0246 (119/4828). AF 95% confidence interval is 0.0217. There are 40 homozygotes in GnomAd4. There are 1335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.7504G>A	p.Gly2502Ser	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.7588G>A	p.Gly2530Ser	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.7558G>A	p.Gly2520Ser	missense	Exon 17 of 17	NP_001341825.1	R4GMU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.7504G>A	p.Gly2502Ser	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.7504G>A	p.Gly2502Ser	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
	ENSG00000258864	ENST00000520401.1	TSL:3	n.229-13551G>A		intron	N/A	ENSP00000454861.1	H3BNH8

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2589 AN: 152140 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0197 AC: 4951 AN: 251266 AF XY: 0.0206

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.00793

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0422

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0203 AC: 29606 AN: 1461704 Hom.: 372 Cov.: 34 AF XY: 0.0205 AC XY: 14934 AN XY: 727160

African (AFR) AF: 0.00272 AC: 91 AN: 33474

American (AMR) AF: 0.00836 AC: 374 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 271 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0265 AC: 2288 AN: 86248

European-Finnish (FIN) AF: 0.0393 AC: 2101 AN: 53416

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5768

European-Non Finnish (NFE) AF: 0.0208 AC: 23133 AN: 1111858

Other (OTH) AF: 0.0205 AC: 1236 AN: 60388

GnomAD4 genome AF: 0.0170 AC: 2589 AN: 152258 Hom.: 40 Cov.: 32 AF XY: 0.0179 AC XY: 1335 AN XY: 74440

African (AFR) AF: 0.00428 AC: 178 AN: 41554

American (AMR) AF: 0.0150 AC: 229 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0246 AC: 119 AN: 4828

European-Finnish (FIN) AF: 0.0402 AC: 426 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1542 AN: 68012

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0194 Hom.: 135

Bravo AF: 0.0137

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0198 AC: 2410

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0206

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Familial adenomatous polyposis 1 (3)
-	-	3	not provided (3)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Familial multiple polyposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.29	N
PhyloP100		4.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.030	N
REVEL	Uncertain	0.32
Sift	Benign	0.30	T
Sift4G	Benign	0.53	T
Polyphen		0.15	B
Vest4		0.12
ClinPred		0.0096	T
GERP RS		6.0
Varity_R		0.060
gMVP		0.36
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229995; hg19: chr5-112178795; COSMIC: COSV57321498; COSMIC: COSV57321498;