5-112821904-C-G

Position:

• chr5-112821904-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000038.6(APC):​c.1321C>G​(p.Pro441Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,174 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.1321C>G	p.Pro441Ala	missense_variant	11/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1321C>G	p.Pro441Ala	missense_variant	11/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460174 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 14, 2019

Variant summary: APC c.1321C>G (p.Pro441Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245278 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1321C>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2020

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 proline with alanine at codon 441 of the APC protein (p.Pro441Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The p.P441A variant (also known as c.1321C>G), located in coding exon 10 of the APC gene, results from a C to G substitution at nucleotide position 1321. The proline at codon 441 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, in silico predictors for this gene do not accurately predict pathogenicity. 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	0.13
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	.;D;D;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.5	.;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.7	D;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.033	D;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.20	.;B;B;.
Vest4		0.58, 0.70
MutPred		0.40		.;Loss of catalytic residue at P441 (P = 0.0449);Loss of catalytic residue at P441 (P = 0.0449);Loss of catalytic residue at P441 (P = 0.0449);
MVP		0.56
ClinPred		0.92	D
GERP RS		6.2
Varity_R		0.87
gMVP		0.41

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: rs1444245614; hg19: chr5-112157601;