5-112707788-C-G

Variant names:

• chr5-112707788-C-G
• rs770241997
• NM_001407446.1:c.71C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001407446.1(APC):​c.71C>G​(p.Ser24Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000821 in 1,218,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S24F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: APC NM_001407446.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0590
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123722285).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407446.1. 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_001407446.1		c.71C>G	p.Ser24Cys	missense	Exon 1 of 16	NP_001394375.1
	APC	NM_001354897.2		c.71C>G	p.Ser24Cys	missense	Exon 1 of 15	NP_001341826.1
	APC	NM_001127511.3		c.71C>G	p.Ser24Cys	missense	Exon 1 of 14	NP_001120983.2	P25054-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000507379.6	TSL:2	c.71C>G	p.Ser24Cys	missense	Exon 1 of 14	ENSP00000423224.2	P25054-3
	APC	ENST00000951167.1		c.-19+139C>G		intron	N/A	ENSP00000621226.1
	APC	ENST00000509732.6	TSL:4	c.-19+139C>G		intron	N/A	ENSP00000426541.2	P25054-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.21e-7 AC: 1 AN: 1218368 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 595224

African (AFR) AF: 0.00 AC: 0 AN: 28310

American (AMR) AF: 0.00 AC: 0 AN: 30760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21054

East Asian (EAS) AF: 0.00 AC: 0 AN: 24244

South Asian (SAS) AF: 0.00 AC: 0 AN: 76906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4894

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 970780

Other (OTH) AF: 0.00 AC: 0 AN: 48296

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial adenomatous polyposis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	13
DANN	Benign	0.95
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.35	T
PhyloP100		-0.059
PROVEAN	Benign	0.13	N
REVEL	Benign	0.14
Sift	Uncertain	0.013	D
MutPred		0.25		Loss of phosphorylation at S24 (P = 0.043)
MVP		0.77
ClinPred		0.21	T
GERP RS		1.1
PromoterAI		0.0041	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770241997; hg19: chr5-112043485;