rs730881233

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM5PP3BS2

The NM_000038.6(APC):c.1241G>A(p.Arg414His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,756 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. R414C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 10.0

Variant links:

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]

APC links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-112819272-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.1241G>A	p.Arg414His	missense_variant	10/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1241G>A	p.Arg414His	missense_variant	10/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250586

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000203

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000157

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 17, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 414 of the APC protein (p.Arg414His). This variant is present in population databases (rs730881233, gnomAD 0.02%). This missense change has been observed in individual(s) with neuroblastoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 181785). 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%. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 17, 2022	This missense variant replaces arginine with histidine at codon 414 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 8/250586 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 26, 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, criteria provided, single submitter	curation	Sema4, Sema4	Oct 11, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with neuroblastoma and in an individual with osteosarcoma (PMID: 26580448, 32191290); This variant is associated with the following publications: (PMID: 32231684, 26580448, 32191290) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 10, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 16, 2018

Variant summary: APC c.1241G>A (p.Arg414His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245360 control chromosomes, predominantly at a frequency of 0.00021 within the Latino subpopulation in the gnomAD database, which is 3-folds over the estimated maximum expected allele frequency for a pathogenic APC variant. Therefore, suggesting the variant is a benign polymorphism found predominantly in population(s) of Latino origin. c.1241G>A has not been reported in the literature in individuals affected with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 15, 2022

- -

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

Dec 01, 2023

This missense variant replaces arginine with histidine at codon 414 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with neuroblastoma in the literature (PMID: 26580448). This variant has been identified in 8/250586 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. -

APC-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2024

The APC c.1241G>A variant is predicted to result in the amino acid substitution p.Arg414His. This variant was reported in an individual with neuroblastoma (Zhang et al 2015. PubMed ID: 26580448). This variant was also reported in an individual with osteosarcoma (eTable 5, Mirabello et al 2020. PubMed ID: 32191290). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. In ClinVar the p.Arg414His variant is classified as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/181785/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;D;D;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.;D;D

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.6

.;L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Benign

0.10

T;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.93, 0.83

MutPred

0.67

.;Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);

MVP

0.81

ClinPred

0.87

GERP RS

5.9

Varity_R

0.76

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over