rs1060503324

Variant names:

• chr5-112841355-G-A
• rs1060503324
• NM_000038.6:c.5761G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112841355-G-A
• chr5-112841355-G-C
• chr5-112841355-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. BS2_Supporting PM2_Supporting BP1 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5761G>A variant in APC is a missense variant predicted to cause the substitution of glycine by serine at amino acid position 1921 (p.Gly1921Ser). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). This variant has been observed in more than 3 heterozygous individuals with no features of FAP, worth 3 healthy individual points (BS2_Supporting; Ambry Genetics internal data). A luciferase reporter plasmid transiently transfected into SW480 cells shows an inability to suppress beta-catenin-regulated transcription indicating that this variant impacts protein function (PS3_Supporting; PMID 18199528). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to conflicting evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2_supporting, BP1, PM2_supporting, and PS3_supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CV411472/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 1.20
• Publications: 1 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

ENSG00000258864 (HGNC:):

ACMG classification

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

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

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.5761G>A	p.Gly1921Ser	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.5845G>A	p.Gly1949Ser	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.5815G>A	p.Gly1939Ser	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.5761G>A	p.Gly1921Ser	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.5761G>A	p.Gly1921Ser	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
	APC	ENST00000508624.5	TSL:1	n.*5083G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000424265.1	E7EMH9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.2
DANN	Benign	0.83
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.32	N
REVEL	Uncertain	0.46
Sift	Benign	0.33	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.65
MutPred		0.74		Gain of phosphorylation at G1921 (P = 0.0309)
MVP		0.95
ClinPred		0.068	T
GERP RS		2.2
Varity_R		0.019
gMVP		0.23
Mutation Taster		=12/88	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: rs1060503324; hg19: chr5-112177052;