rs1114167617

Variant names:

• chr5-112838677-G-A
• rs1114167617
• NM_000038.6:c.3083G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112838677-G-A
• chr5-112838677-G-C
• chr5-112838677-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2_Supporting PS4_Moderate PM5_Supporting PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000038.6:c.3083G>A variant in APC is a missense variant predicted to cause the substitution of serine to asparagine at amino acid position 1028 (p.Ser1028Asn). This variant has been reported in 4 probands/families meeting phenotypic criteria, resulting in a total phenotype score of 2 (PS4_Moderate; internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and one individual with colorectal cancer in the family history (internal data Ambry Genetics; Labcorp Genetics (formerly Invitae); Peter MacCallum Cancer Centre, Victoria, Australia). This variant has been reported to segregate with FAP in 5 meioses in 2 families (PP1_Moderate; internal data Ambry Genetics and Peter MacCallum Cancer Centre, Victoria, Australia). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants (c.3084T>A and c.3083G>T) in the same codon leading to a different amino acid change at this position (p.Ser1028Arg; p.Ser1028Ile) have been classified as Likely Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PS4_Moderate, PP1_Moderate, PM2_Supporting and PM5_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16028084/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_001407446.1 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.36
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

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_000038.6	MANE Select	c.3083G>A	p.Ser1028Asn	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.3167G>A	p.Ser1056Asn	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.3137G>A	p.Ser1046Asn	missense	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.3083G>A	p.Ser1028Asn	missense	Exon 16 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.3083G>A	p.Ser1028Asn	missense	Exon 17 of 17	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.*1281G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Familial adenomatous polyposis 1 (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N
PhyloP100		9.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.72		Loss of phosphorylation at S1028 (P = 0.1007)
MVP		0.91
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.77
Mutation Taster		=35/65	disease causing (ClinVar)

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: rs1114167617; hg19: chr5-112174374;