5-112844030-C-G

Variant names:

• chr5-112844030-C-G
• rs750971628
• NM_000038.6:c.8436C>G

Variant summary

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

The NM_000038.6(APC):​c.8436C>G​(p.Asn2812Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2812S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• 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: 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• 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: 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=0.13280737).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.8436C>G	p.Asn2812Lys	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.8520C>G	p.Asn2840Lys	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.8490C>G	p.Asn2830Lys	missense	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.8436C>G	p.Asn2812Lys	missense	Exon 16 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.8436C>G	p.Asn2812Lys	missense	Exon 17 of 17	ENSP00000427089.2
	ENSG00000258864	ENST00000520401.1	TSL:3	n.229-12619C>G		intron	N/A	ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237772 AF XY: 0.00000779

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.10	T
Polyphen		0.027	B
Vest4		0.19
MutPred		0.38		Gain of methylation at N2812 (P = 0.0028)
MVP		0.80
ClinPred		0.29	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.21
Mutation Taster		=67/33	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: rs750971628; hg19: chr5-112179727;