5-112819324-T-G

Variant names:

• chr5-112819324-T-G
• rs1034113927
• NM_000038.6:c.1292T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000038.6(APC):​c.1292T>G​(p.Met431Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M431V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.76
• Publications: 8 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: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

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

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

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112819324-T-G is Pathogenic according to our data. Variant chr5-112819324-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 654705.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24985376). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1292T>G	p.Met431Arg	missense_variant	Exon 10 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1292T>G	p.Met431Arg	missense_variant	Exon 10 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 11, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1292T>G variant (also known as p.M431R), located in coding exon 9 of the APC gene, results from a T to G substitution at nucleotide position 1292. The methionine at codon 431 is replaced by arginine, an amino acid with similar properties. This variant was reported in an individual with features consistent with APC-related familial adenomatous polyposis (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. However, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial adenomatous polyposis 1 Uncertain:1

Dec 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with APC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with arginine at codon 431 of the APC protein (p.Met431Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.41	.;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.068
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Benign	0.69	.;N;N;.
PhyloP100		4.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.51	T;T;T;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.22	.;B;B;.
Vest4		0.75, 0.83
MutPred		0.40		.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.98
ClinPred		0.44	T
GERP RS		5.8
Varity_R		0.79
gMVP		0.72
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1034113927; hg19: chr5-112155021;