NM_000038.6:c.646-2A>T

Variant names:

• chr5-112792444-A-T
• rs777848503
• NM_000038.6:c.646-2A>T

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModeratePS1PM2

The NM_000038.6(APC):c.646-2A>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. This is a canonical splice-site variant (loss-of-function). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.46
• 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

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: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Non-NMD splice frameshift: disease mechanism, small exon — moderate (PVS1 downgraded to PM); Splice acceptor variant predicted to cause a frameshift; NMD not predicted. Loss of function is a known disease mechanism, but the exon is small.
	PS1Same amino acid change as known pathogenic		Splice site has a more-destructive ClinVar pathogenic — strong (PS1); A more pathogenic splice-site variant at the same position has been reported in ClinVar.
	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.646-2A>T	splice_acceptorintron	Intron 6 of 15	Prot: NP_000029.2
	APC NM_001407446.1		c.676-2A>T	splice_acceptorintron	Intron 5 of 15	Prot: NP_001394375.1
	APC NM_001354896.2		c.646-2A>T	splice_acceptorintron	Intron 6 of 16	Prot: NP_001341825.1 UniProt:

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.646-2A>T

Exon rankIntron 6 of 15

splice_acceptorintron

Prot: NP_000029.2

APC NM_001407446.1

HGVSc / HGVSpc.676-2A>T

Exon rankIntron 5 of 15

splice_acceptorintron

Prot: NP_001394375.1

APC NM_001354896.2

HGVSc / HGVSpc.646-2A>T

Exon rankIntron 6 of 16

splice_acceptorintron

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.646-2A>T	splice_acceptorintron	Intron 6 of 15	Prot: ENSP00000257430.4 UniProt:
	APC ENST00000508376.6	TSL:1	c.646-2A>T	splice_acceptorintron	Intron 7 of 16	Prot: ENSP00000427089.2 UniProt:
	APC ENST00000502371.3	TSL:1	n.646-2A>T	splice_acceptorintron	Intron 5 of 11	Prot: ENSP00000484935.2 UniProt:

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.646-2A>T

Exon rankIntron 6 of 15

splice_acceptorintron

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.646-2A>T

Exon rankIntron 7 of 16

splice_acceptorintron

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000502371.3

TSL:1

HGVSc / HGVSpn.646-2A>T

Exon rankIntron 5 of 11

splice_acceptorintron

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:29
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
Mutation Taster	N/A	2/98	disease causing
PhyloP100	Uncertain	6.5

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
DS_AG_spliceai	Pathogenic	0.95	Position offset: 12
DS_AL_spliceai	Pathogenic	1.0	Position offset: 2
Pangolin (max)	Pathogenic	0.88
Pangolin gain	Pathogenic	0.77	Position offset: 7
Pangolin loss	Pathogenic	0.88	Position offset: 2
SpliceAI score (max)	Pathogenic	1.0	Details are displayed if max score is > 0.2

Showing 8 of 8 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: rs777848503;

hg19: chr5-112128141;

COSMIC: COSV57346431;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar