5-112840862-T-G

Variant names:

• chr5-112840862-T-G
• rs866006
• NM_000038.6:c.5268T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000038.6(APC):​c.5268T>G​(p.Ser1756Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,613,728 control chromosomes in the GnomAD database, including 319,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1756S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.60 (28136 hom., cov: 32)
  • Exomes 𝑓: 0.63 (291657 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 0.169
• Publications: 73 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-112840862-T-G is Benign according to our data. Variant chr5-112840862-T-G is described in ClinVar as Benign. ClinVar VariationId is 42245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.169 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

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.5268T>G	p.Ser1756Ser	synonymous	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.5352T>G	p.Ser1784Ser	synonymous	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.5322T>G	p.Ser1774Ser	synonymous	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.5268T>G	p.Ser1756Ser	synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.5268T>G	p.Ser1756Ser	synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000508624.5	TSL:1	n.*4590T>G		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91592 AN: 151940 Hom.: 28119 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.615

GnomAD2 exomes AF: 0.651 AC: 163104 AN: 250444 AF XY: 0.651

Gnomad AFR exome AF: 0.534

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.821

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.650

GnomAD4 exome AF: 0.629 AC: 919568 AN: 1461670 Hom.: 291657 Cov.: 70 AF XY: 0.631 AC XY: 458889 AN XY: 727132

African (AFR) AF: 0.521 AC: 17447 AN: 33470

American (AMR) AF: 0.727 AC: 32521 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 15451 AN: 26134

East Asian (EAS) AF: 0.840 AC: 33361 AN: 39698

South Asian (SAS) AF: 0.710 AC: 61229 AN: 86250

European-Finnish (FIN) AF: 0.574 AC: 30637 AN: 53402

Middle Eastern (MID) AF: 0.616 AC: 3555 AN: 5768

European-Non Finnish (NFE) AF: 0.618 AC: 687033 AN: 1111840

Other (OTH) AF: 0.635 AC: 38334 AN: 60388

GnomAD4 genome AF: 0.603 AC: 91661 AN: 152058 Hom.: 28136 Cov.: 32 AF XY: 0.604 AC XY: 44907 AN XY: 74318

African (AFR) AF: 0.535 AC: 22185 AN: 41450

American (AMR) AF: 0.669 AC: 10226 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1991 AN: 3468

East Asian (EAS) AF: 0.819 AC: 4247 AN: 5184

South Asian (SAS) AF: 0.731 AC: 3522 AN: 4820

European-Finnish (FIN) AF: 0.536 AC: 5662 AN: 10556

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.615 AC: 41788 AN: 67984

Other (OTH) AF: 0.613 AC: 1294 AN: 2112

Alfa AF: 0.608 Hom.: 38634

Bravo AF: 0.611

Asia WGS AF: 0.755 AC: 2622 AN: 3478

EpiCase AF: 0.612

EpiControl AF: 0.615

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	Familial adenomatous polyposis 1 (2)
-	-	2	not provided (2)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	-	Familial colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.24
DANN	Benign	0.52
PhyloP100		0.17
Mutation Taster		=98/2	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: rs866006; hg19: chr5-112176559; COSMIC: COSV57321636; COSMIC: COSV57321636;