NM_000038.6:c.4348_4350delCGAinsGGC

Variant names:

• chr5-112839942-CGA-GGC
• NM_000038.6:c.4348_4350delCGAinsGGC
• APC p.Arg1450Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000038.6(APC):c.4348_4350delCGAinsGGC (p.Arg1450Gly) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1450G: Uncertain_significance (ClinVar VariationId 1503074, 1 star); p.R1450L: Uncertain_significance (ClinVar VariationId 537491, 2 stars); p.R1450P: Uncertain_significance (ClinVar VariationId 921852, 2 stars); p.R1450Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 142731); p.R1450= (synonymous): Likely_benign (ClinVar VariationId 1110103, 2 stars) The variant position is a cancer hotspot (cancerhotspots.org) with 58 samples affected at this amino acid position. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• 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: Genomics England PanelApp, G2P
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00124) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APC NM_000038.6	MANE Select	c.4348_4350delCGAinsGGC p.Arg1450Gly	missense	N/A	Prot: NP_000029.2
	APC NM_001407446.1		c.4432_4434delCGAinsGGC p.Arg1478Gly	missense	N/A	Prot: NP_001394375.1
	APC NM_001354896.2		c.4402_4404delCGAinsGGC p.Arg1468Gly	missense	N/A	Prot: NP_001341825.1 UniProt:

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.4348_4350delCGAinsGGCp.Arg1450Gly

Exon rankN/A

missense

Prot: NP_000029.2

APC NM_001407446.1

HGVSc / HGVSpc.4432_4434delCGAinsGGCp.Arg1478Gly

Exon rankN/A

missense

Prot: NP_001394375.1

APC NM_001354896.2

HGVSc / HGVSpc.4402_4404delCGAinsGGCp.Arg1468Gly

Exon rankN/A

missense

Prot: NP_001341825.1UniProt: R4GMU6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APC ENST00000257430.9	TSL:5MANE Select	c.4348_4350delCGAinsGGC p.Arg1450Gly	missense	N/A	Prot: ENSP00000257430.4 UniProt:
	APC ENST00000508376.6	TSL:1	c.4348_4350delCGAinsGGC p.Arg1450Gly	missense	N/A	Prot: ENSP00000427089.2 UniProt:
	APC ENST00000508624.5	TSL:1	n.*3670_*3672delCGAinsGGC	3_prime_UTR	Exon 17 of 17	Prot: ENSP00000424265.1 UniProt:

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.4348_4350delCGAinsGGCp.Arg1450Gly

Exon rankN/A

missense

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.4348_4350delCGAinsGGCp.Arg1450Gly

Exon rankN/A

missense

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000508624.5

TSL:1

HGVSc / HGVSpn.*3670_*3672delCGAinsGGC

Exon rankExon 17 of 17

3_prime_UTR

Prot: ENSP00000424265.1UniProt: E7EMH9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	3.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr5-112175639;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar