5-112767189-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000038.6(APC):c.221A>G(p.Glu74Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E74A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense, splice_region
• Scores: Splicing: ADA: 0.1755
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.37

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-112766410-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.26349214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.221A>G	p.Glu74Gly	missense_variant, splice_region_variant	4/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.221A>G	p.Glu74Gly	missense_variant, splice_region_variant	4/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460002 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726498

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 74 of the APC protein (p.Glu74Gly). This variant is not present in population databases (gnomAD no frequency). 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"). ClinVar contains an entry for this variant (Variation ID: 485134). This variant has not been reported in the literature in individuals affected with APC-related conditions. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2019

The p.E74G variant (also known as c.221A>G) is located in coding exon 3 of the APC gene. The glutamic acid at codon 74 is replaced by glycine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 3. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This position was not covered in the ESP. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 90000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T;T;T
Eigen	Benign	0.032
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D;D;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.085	T;D;T;T;D
Sift4G	Uncertain	0.012	D;T;T;T;T
Polyphen		0.046	.;.;B;B;.
Vest4		0.68, 0.66
MutPred		0.10		Gain of MoRF binding (P = 0.0784);.;Gain of MoRF binding (P = 0.0784);Gain of MoRF binding (P = 0.0784);Gain of MoRF binding (P = 0.0784);
MVP		0.95
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.39
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: rs773347338; hg19: chr5-112102886;