chr5-112839942-C-G

Variant names:

• chr5-112839942-C-G
• rs121913332
• NM_000038.6:c.4348C>G
• APC p.Arg1450Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000038.6(APC):c.4348C>G (p.Arg1450Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,874 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21
• Publications: 77 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 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00124) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (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.4348C>G p.Arg1450Gly	missense	Exon 16 of 16	Prot: NP_000029.2
	APC NM_001407446.1		c.4432C>G p.Arg1478Gly	missense	Exon 16 of 16	Prot: NP_001394375.1
	APC NM_001354896.2		c.4402C>G p.Arg1468Gly	missense	Exon 17 of 17	Prot: NP_001341825.1 UniProt:

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.4348C>Gp.Arg1450Gly

Exon rankExon 16 of 16

missense

Prot: NP_000029.2

APC NM_001407446.1

HGVSc / HGVSpc.4432C>Gp.Arg1478Gly

Exon rankExon 16 of 16

missense

Prot: NP_001394375.1

APC NM_001354896.2

HGVSc / HGVSpc.4402C>Gp.Arg1468Gly

Exon rankExon 17 of 17

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.4348C>G p.Arg1450Gly	missense	Exon 16 of 16	Prot: ENSP00000257430.4 UniProt:
	APC ENST00000508376.6	TSL:1	c.4348C>G p.Arg1450Gly	missense	Exon 17 of 17	Prot: ENSP00000427089.2 UniProt:
	APC ENST00000508624.5	TSL:1	n.*3670C>G	3_prime_UTR	Exon 17 of 17	Prot: ENSP00000424265.1 UniProt:

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.4348C>Gp.Arg1450Gly

Exon rankExon 16 of 16

missense

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.4348C>Gp.Arg1450Gly

Exon rankExon 17 of 17

missense

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000508624.5

TSL:1

HGVSc / HGVSpn.*3670C>G

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251172	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461874	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122630	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000149	1	67158	0.00	0	132346

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial adenomatous polyposis 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
FuncVEP CTI	Benign	0.0023
GPN-Star LLR	N/A	-6.0
GPN-Star score	N/A	6.0
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.011	D
Mutation Taster	N/A	50/50
MutationAssessor	Benign	0.90	L
PhyloP100	Benign	3.2
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.18
Sift	Benign	0.54	T
Sift4G	Benign	0.54	T
Varity_R	N/A	0.082
VESM-3B	Benign	-3.4

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs121913332;

hg19: chr5-112175639;

COSMIC: COSV105854597;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar