5-112841395-C-T

Variant names:

• chr5-112841395-C-T
• rs587780600
• NM_000038.6:c.5801C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000038.6(APC):​c.5801C>T​(p.Pro1934Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1934R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:12
• Conservation: PhyloP100: 3.67
• Publications: 8 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24149853).
• BP6: Variant 5-112841395-C-T is Benign according to our data. Variant chr5-112841395-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135709.

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.5801C>T	p.Pro1934Leu	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.5885C>T	p.Pro1962Leu	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.5855C>T	p.Pro1952Leu	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.5801C>T	p.Pro1934Leu	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.5801C>T	p.Pro1934Leu	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000508624.5	TSL:1	n.*5123C>T		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000144 AC: 36 AN: 249974 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461568 Hom.: 0 Cov.: 65 AF XY: 0.000153 AC XY: 111 AN XY: 727120

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.000380 AC: 17 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000152 AC: 169 AN: 1111772

Other (OTH) AF: 0.000199 AC: 12 AN: 60386

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74448

African (AFR) AF: 0.0000241 AC: 1 AN: 41538

American (AMR) AF: 0.000196 AC: 3 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	2	1	not specified (3)
-	-	2	Familial adenomatous polyposis 1 (2)
-	1	-	APC-Associated Polyposis Disorders (1)
-	-	1	APC-related disorder (1)
-	1	-	Classic or attenuated familial adenomatous polyposis (1)
-	1	-	Colorectal cancer, susceptibility to (1)
-	1	-	Familial multiple polyposis syndrome (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)
-	-	1	Hereditary cancer (1)
-	1	-	Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.050	T
Polyphen		0.38	B
Vest4		0.71
MVP		0.97
ClinPred		0.062	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.51
Mutation Taster		=4/96	disease causing

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: rs587780600; hg19: chr5-112177092; COSMIC: COSV105082476;