rs371085910

chr5-112775655-A-Gchr5-112775655-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP3 BP6 BS2

The NM_000038.6(APC):c.449A>G(p.Lys150Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,608,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. K150I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:3
• Conservation: PhyloP100: 8.56

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.

• PM1: In a helix (size 37) in uniprot entity APC_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000038.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• BP6: Variant 5-112775655-A-G is Benign according to our data. Variant chr5-112775655-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141928.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Likely_benign=3}.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.449A>G	p.Lys150Arg	missense_variant	5/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.449A>G	p.Lys150Arg	missense_variant	5/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247824 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000639 AC: 93 AN: 1456346 Hom.: 0 Cov.: 29 AF XY: 0.0000552 AC XY: 40 AN XY: 724230

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: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000793

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74286

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000861 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 150 of the APC protein (p.Lys150Arg). This variant is present in population databases (rs371085910, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 141928). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 17, 2023	This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 29, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This missense variant replaces lysine with arginine at codon 150 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer, colorectal adenomas, and rhabdosarcoma in the literature (PMID: 18199528, 21859464, 26580448, 28503720). This variant has been identified in 6/279048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 10, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 25, 2017	- -

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 22, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2018	Variant summary: APC c.449A>G (p.Lys150Arg) results in a 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 allele was found at a frequency of 2.2e-05 in 273686 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2.2e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.449A>G has been reported in the literature in individuals affected with breast cancer and colon colorectal adenomas (Azzopardi_2008, Rummel_2017). These reports do not provide unequivocal conclusions about an association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2022	Observed in individuals with a personal history of colorectal adenomas, breast cancer, or other cancers (Azzopardi et al., 2008; Minde et al., 2011; Zhang et al., 2015; Ballinger et al., 2016; Rummel et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25637381, 21859464, 18199528, 26580448, 27498913, 28152038, 28503720, 16454848, 12070164, 27535533, 11257105, 34301788) -

Classic or attenuated familial adenomatous polyposis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces lysine with arginine at codon 150 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer, colorectal adenomas, and rhabdosarcoma in the literature (PMID: 18199528, 21859464, 26580448, 28503720). This variant has been identified in 6/279048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Colorectal adenoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Pathogenic	0.87
Sift	Benign	0.047	D;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.51	.;P;P;.
Vest4		0.73, 0.76
MVP		0.99
ClinPred		0.46	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -26

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

Publications

LitVar

Other links and lift over

dbSNP: rs371085910; hg19: chr5-112111352;