chr5-112801313-A-G

Variant names:

• chr5-112801313-A-G
• rs530670052
• NM_000038.6:c.764A>G
• APC p.His255Arg

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4BP6

The NM_000038.6(APC):c.764A>G (p.His255Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000353 (AC=57) in the gnomAD database across 1,612,982 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000655. 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 Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H255= (synonymous): Likely_benign (ClinVar VariationId 1101103, 2 stars); p.H255L: Uncertain_significance (ClinVar VariationId 3410081, 2 stars); p.H255P: Uncertain_significance (ClinVar VariationId 3882679, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 2.09
• 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: 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_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000655 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00124) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.764A>G p.His255Arg	missense	Exon 8 of 16	Prot: NP_000029.2
	APC NM_001407446.1		c.794A>G p.His265Arg	missense	Exon 7 of 16	Prot: NP_001394375.1
	APC NM_001354896.2		c.764A>G p.His255Arg	missense	Exon 8 of 17	Prot: NP_001341825.1 UniProt:

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.764A>Gp.His255Arg

Exon rankExon 8 of 16

missense

Prot: NP_000029.2

APC NM_001407446.1

HGVSc / HGVSpc.794A>Gp.His265Arg

Exon rankExon 7 of 16

missense

Prot: NP_001394375.1

APC NM_001354896.2

HGVSc / HGVSpc.764A>Gp.His255Arg

Exon rankExon 8 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.764A>G p.His255Arg	missense	Exon 8 of 16	Prot: ENSP00000257430.4 UniProt:
	APC ENST00000508376.6	TSL:1	c.764A>G p.His255Arg	missense	Exon 9 of 17	Prot: ENSP00000427089.2 UniProt:
	APC ENST00000502371.3	TSL:1	n.764A>G	non_coding_transcript_exon	Exon 7 of 12	Prot: ENSP00000484935.2 UniProt:

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.764A>Gp.His255Arg

Exon rankExon 8 of 16

missense

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.764A>Gp.His255Arg

Exon rankExon 9 of 17

missense

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000502371.3

TSL:1

HGVSc / HGVSpn.764A>G

Exon rankExon 7 of 12

non_coding_transcript_exon

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: 0.0000131	AC:2	Hom:0	AN:152218	Cov:32
GnomAD2 exomes	AF: 0.0000159	AC:4	Hom:	AN:251096	Cov:
GnomAD4 exome	AF: 0.0000377	AC:55	Hom:0	AN:1460764	Cov:30
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152218	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000510	AC:4	Hom:0	AN:78408	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28412	0.0000694	2	28834
Epi25(Epilepsy)	0.0000238	1	41938	0.0000452	3	66374
SCHEMA(Schizophrenia)	0.0000268	3	111934	0.0000217	4	184208

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	1	not specified (2)
-	1	-	APC-related disorder (1)
-	1	-	Classic or attenuated familial adenomatous polyposis (1)
-	1	-	Familial adenomatous polyposis 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
AlphaMissense	Benign	0.058
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.037
FATHMM_MKL	Benign	0.74	D
FuncVEP CTI	Benign	0.00075
GPN-Star LLR	N/A	-2.5
GPN-Star score	N/A	2.5
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.22	T
Mutation Taster	N/A	72/28	polymorphism
MutationAssessor	Benign	0.90	L
PhyloP100	Benign	2.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.33	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.24
Sift	Benign	0.17	T
Sift4G	Benign	0.56	T
Varity_R	N/A	0.060
VESM-3B	Benign	-1.8

Showing 29 of 29 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: rs530670052;

hg19: chr5-112137010;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar