chr5-112843375-C-G

Variant names:

• chr5-112843375-C-G
• rs543396310
• NM_000038.6:c.7781C>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.7781C>G​(p.Ser2594Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,613,748 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. S2594Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.958
• Publications: 4 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=0.0055871904).
• BP6: Variant 5-112843375-C-G is Benign according to our data. Variant chr5-112843375-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 350422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000185 (270/1461490) while in subpopulation SAS AF = 0.00288 (248/86218). AF 95% confidence interval is 0.00258. There are 3 homozygotes in GnomAdExome4. There are 199 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.7781C>G	p.Ser2594Cys	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.7865C>G	p.Ser2622Cys	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.7835C>G	p.Ser2612Cys	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.7781C>G	p.Ser2594Cys	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.7781C>G	p.Ser2594Cys	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
	ENSG00000258864	ENST00000520401.1	TSL:3	n.229-13274C>G		intron	N/A	ENSP00000454861.1	H3BNH8

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000423 AC: 106 AN: 250650 AF XY: 0.000576

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000185 AC: 270 AN: 1461490 Hom.: 3 Cov.: 34 AF XY: 0.000274 AC XY: 199 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00288 AC: 248 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111752

Other (OTH) AF: 0.000182 AC: 11 AN: 60386

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74444

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.000478 AC: 58

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial adenomatous polyposis 1 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	APC-Associated Polyposis Disorders (1)
-	-	1	APC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.96
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0	B
Vest4		0.089
MutPred		0.30		Loss of phosphorylation at S2594 (P = 0.0158)
MVP		0.78
ClinPred		0.022	T
GERP RS		3.2
Varity_R		0.090
gMVP		0.34
Mutation Taster		=86/14	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: rs543396310; hg19: chr5-112179072; COSMIC: COSV57344361;