5-112801349-G-C

Variant names:

• chr5-112801349-G-C
• rs747759906
• NM_000038.6:c.800G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000038.6(APC):​c.800G>C​(p.Gly267Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06356126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.800G>C	p.Gly267Ala	missense_variant	Exon 8 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.800G>C	p.Gly267Ala	missense_variant	Exon 8 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Nov 11, 2019

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 495375). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 267 of the APC protein (p.Gly267Ala). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and alanine. -

not provided Uncertain:1

Jun 23, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The APC c.800G>C (p.Gly267Ala) variant involves the alteration of a conserved nucleotide, resulting in a missense change within the pyridoxal phosphate-dependent transferase, major region, subdomain 1 (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to non-functioning tool). This variant is absent from the large database ExAC (0/120038 control chromosomes). To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.12
DEOGEN2	Benign	0.34	.;T;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.53	T;.;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.83	.;N;N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.81	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.76	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.11, 0.14
MutPred		0.23		.;Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);
MVP		0.57
ClinPred		0.062	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs747759906; hg19: chr5-112137046;