rs1060503275

Variant names:

• chr5-112844032-C-A
• rs1060503275
• NM_000038.6:c.8438C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112844032-C-A
• chr5-112844032-C-G
• chr5-112844032-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. BS2_Supporting PM2_Supporting BP1

This summary comes from the ClinGen Evidence Repository: The c.8438C>A variant in APC is a missense variant predicted to cause the substitution of Threonine by Lysine at amino acid position 2813 (p.Thr2813Lys). This variant has been observed in ≥ 3 individuals with no features or family history of FAP, which is worth 3 healthy individual points (BS2_supporting; Invitae and Ambry internal data). 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 is absent from gnomAD v2.1.1 (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Benign for FAP. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS2_supporting, and BP1. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CV411374/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:1
• Conservation: PhyloP100: 5.39
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• 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.8438C>A	p.Thr2813Lys	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.8522C>A	p.Thr2841Lys	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.8492C>A	p.Thr2831Lys	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.8438C>A	p.Thr2813Lys	missense	Exon 16 of 16	ENSP00000257430.4	P25054-1
	APC	ENST00000508376.6	TSL:1	c.8438C>A	p.Thr2813Lys	missense	Exon 17 of 17	ENSP00000427089.2	P25054-1
	ENSG00000258864	ENST00000520401.1	TSL:3	n.229-12617C>A		intron	N/A	ENSP00000454861.1	H3BNH8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450384 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 721204

African (AFR) AF: 0.00 AC: 0 AN: 32606

American (AMR) AF: 0.00 AC: 0 AN: 41638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25422

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 83584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108848

Other (OTH) AF: 0.00 AC: 0 AN: 59788

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.15	T
Polyphen		0.96	D
Vest4		0.44
MutPred		0.46		Gain of methylation at T2813 (P = 0.0026)
MVP		0.83
ClinPred		0.70	D
GERP RS		5.9
Varity_R		0.39
gMVP		0.35
Mutation Taster		=24/76	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: rs1060503275; hg19: chr5-112179729;