rs33974176

Variant names:

• chr5-112838202-C-T
• rs33974176
• NM_000038.6:c.2608C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-112838202-C-T
• chr5-112838202-C-A
• chr5-112838202-C-G

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.2608C>T​(p.Pro870Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,126 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. P870delinsFFKA) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (24 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25 O:1
• Conservation: PhyloP100: -0.617
• Publications: 24 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=0.0030145645).
• BP6: Variant 5-112838202-C-T is Benign according to our data. Variant chr5-112838202-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41500.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 = 0.00851 (1295/152242) while in subpopulation AFR AF = 0.0299 (1240/41540). AF 95% confidence interval is 0.0285. There are 26 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.2608C>T	p.Pro870Ser	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.2692C>T	p.Pro898Ser	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.2662C>T	p.Pro888Ser	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.2608C>T	p.Pro870Ser	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.2608C>T	p.Pro870Ser	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000502371.3	TSL:1	n.*806C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2	A0A087X2F3

Frequencies

GnomAD3 genomes AF: 0.00851 AC: 1294 AN: 152124 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00210 AC: 528 AN: 250946 AF XY: 0.00153

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000916 AC: 1339 AN: 1461884 Hom.: 24 Cov.: 33 AF XY: 0.000784 AC XY: 570 AN XY: 727240

African (AFR) AF: 0.0340 AC: 1137 AN: 33480

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112012

Other (OTH) AF: 0.00197 AC: 119 AN: 60396

GnomAD4 genome AF: 0.00851 AC: 1295 AN: 152242 Hom.: 26 Cov.: 32 AF XY: 0.00826 AC XY: 615 AN XY: 74440

African (AFR) AF: 0.0299 AC: 1240 AN: 41540

American (AMR) AF: 0.00203 AC: 31 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00371 Hom.: 17

Bravo AF: 0.00988

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not provided (5)
-	-	4	Familial adenomatous polyposis 1 (4)
-	-	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	0.059
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.6
DANN	Benign	0.86
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.74	N
PhyloP100		-0.62
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.21
Sift	Benign	0.84	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.094
MVP		0.64
ClinPred		0.0035	T
GERP RS		2.0
Varity_R		0.015
gMVP		0.37
Mutation Taster		=95/5	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: rs33974176; hg19: chr5-112173899; COSMIC: COSV57389158;