chr5-112838773-TAAAAC-T

Variant names:

• chr5-112838773-TAAAAC-T
• rs587779352
• NM_000038.6:c.3183_3187delACAAA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_000038.6(APC):c.3183_3187delACAAA (p.Gln1062fs) variant causes a frameshift change. This is a loss-of-function variant that does not trigger NMD. 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 allele was found at a cumulative frequency of 0.00000274 (AC=4) in the gnomAD database across 1,461,812 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000084. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.72). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). The variant position is a cancer hotspot (cancerhotspots.org) with 13 samples affected at this amino acid position.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:35
• Conservation: PhyloP100: 7.72
• Publications: 4 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: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Non-NMD frameshift: ≥4 downstream pathogenic — very strong evidence preserved (PVS1); Frameshift (exon 16 of 16) at amino acid 1061 of 2843; NMD not predicted. 1207 pathogenic variants downstream support preserved loss-of-function impact. A new stop codon is introduced in the shifted frame, truncating the protein to ~1061 amino acids (1782 amino acids lost).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000084 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00124) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (35/35 total P/LP).

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.3183_3187delACAAA p.Gln1062fs	frameshift	Exon 16 of 16	Prot: NP_000029.2
	APC NM_001407446.1		c.3267_3271delACAAA p.Gln1090fs	frameshift	Exon 16 of 16	Prot: NP_001394375.1
	APC NM_001354896.2		c.3237_3241delACAAA p.Gln1080fs	frameshift	Exon 17 of 17	Prot: NP_001341825.1 UniProt:

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.3183_3187delACAAAp.Gln1062fs

Exon rankExon 16 of 16

frameshift

Prot: NP_000029.2

APC NM_001407446.1

HGVSc / HGVSpc.3267_3271delACAAAp.Gln1090fs

Exon rankExon 16 of 16

frameshift

Prot: NP_001394375.1

APC NM_001354896.2

HGVSc / HGVSpc.3237_3241delACAAAp.Gln1080fs

Exon rankExon 17 of 17

frameshift

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.3183_3187delACAAA p.Gln1062fs	frameshift	Exon 16 of 16	Prot: ENSP00000257430.4 UniProt:
	APC ENST00000508376.6	TSL:1	c.3183_3187delACAAA p.Gln1062fs	frameshift	Exon 17 of 17	Prot: ENSP00000427089.2 UniProt:
	APC ENST00000502371.3	TSL:1	n.*1381_*1385delACAAA	3_prime_UTR	Exon 12 of 12	Prot: ENSP00000484935.2 UniProt:

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.3183_3187delACAAAp.Gln1062fs

Exon rankExon 16 of 16

frameshift

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.3183_3187delACAAAp.Gln1062fs

Exon rankExon 17 of 17

frameshift

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000502371.3

TSL:1

HGVSc / HGVSpn.*1381_*1385delACAAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: ENSP00000484935.2UniProt: A0A087X2F3

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000399	AC:1	Hom:	AN:250490	Cov:
GnomAD4 exome	AF: 0.00000274	AC:4	Hom:0	AN:1461812	Cov:
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.0000151	AC:4	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844

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

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	not provided (14)
13	-	-	Familial adenomatous polyposis 1 (13)
2	-	-	Familial multiple polyposis syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Carcinoma of colon (1)
1	-	-	Classic or attenuated familial adenomatous polyposis (1)
1	-	-	Craniopharyngioma (1)
1	-	-	Inherited polyposis and early onset colorectal cancer - germline testing (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Pathogenic	7.7

Showing 2 of 2 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

dbSNP: rs587779352;

hg19: chr5-112174470;

COSMIC: COSV57331052;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar