rs67622085

Variant names:

• chr5-112839920-T-A
• rs67622085
• NM_000038.6:c.4326T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112839920-T-A
• chr5-112839920-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000038.6(APC):​c.4326T>A​(p.Pro1442Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,842 control chromosomes in the GnomAD database, including 111 homozygotes. 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. P1442P) has been classified as Likely benign. The gene APC is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (103 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.824
• Publications: 21 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

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-112839920-T-A is Benign according to our data. Variant chr5-112839920-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.824 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00736 (1119/151984) while in subpopulation NFE AF = 0.0114 (775/67952). AF 95% confidence interval is 0.0107. There are 8 homozygotes in GnomAd4. There are 502 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.4326T>A	p.Pro1442Pro	synonymous	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.4410T>A	p.Pro1470Pro	synonymous	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.4380T>A	p.Pro1460Pro	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.4326T>A	p.Pro1442Pro	synonymous	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.4326T>A	p.Pro1442Pro	synonymous	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000508624.5	TSL:1	n.*3648T>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 1119 AN: 151866 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00682

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00578

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00719 AC: 1807 AN: 251150 AF XY: 0.00718

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.0113 AC: 16540 AN: 1461858 Hom.: 103 Cov.: 33 AF XY: 0.0111 AC XY: 8044 AN XY: 727224

African (AFR) AF: 0.00185 AC: 62 AN: 33478

American (AMR) AF: 0.00521 AC: 233 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 116 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00191 AC: 165 AN: 86258

European-Finnish (FIN) AF: 0.00696 AC: 372 AN: 53414

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0135 AC: 14988 AN: 1111998

Other (OTH) AF: 0.00965 AC: 583 AN: 60394

GnomAD4 genome AF: 0.00736 AC: 1119 AN: 151984 Hom.: 8 Cov.: 32 AF XY: 0.00676 AC XY: 502 AN XY: 74280

African (AFR) AF: 0.00318 AC: 132 AN: 41462

American (AMR) AF: 0.00681 AC: 104 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4808

European-Finnish (FIN) AF: 0.00578 AC: 61 AN: 10552

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 775 AN: 67952

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00686 Hom.: 1

Bravo AF: 0.00788

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	not provided (4)
-	-	3	Familial adenomatous polyposis 1 (3)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.1
DANN	Benign	0.81
PhyloP100		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

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: rs67622085; hg19: chr5-112175617; COSMIC: COSV57332204; COSMIC: COSV57332204;