rs75239284

chr5-112838589-C-Achr5-112838589-C-Gchr5-112838589-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000038.6(APC):c.2995C>A(p.Gln999Lys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. Q999E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 3.62

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20063838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.2995C>A	p.Gln999Lys	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.2995C>A	p.Gln999Lys	missense_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461822 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727204

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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: 82632). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with lysine at codon 999 of the APC protein (p.Gln999Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. -

Familial colorectal cancer Other:1

other, no assertion criteria provided

literature only

Systems Biology Platform Zhejiang California International NanoSystems Institute

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	19
Dann	Benign	0.87
Eigen	Benign	-0.21
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	0.87	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.52	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.36	T;T;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0050	.;B;B;.
Vest4		0.20, 0.21
MutPred		0.34		.;Gain of ubiquitination at Q999 (P = 0.0051);Gain of ubiquitination at Q999 (P = 0.0051);Gain of ubiquitination at Q999 (P = 0.0051);
MVP		0.96
ClinPred		0.46	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.31

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: rs75239284; hg19: chr5-112174286;