rs76685252

chr5-112792447-G-Achr5-112792447-G-Cchr5-112792447-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000038.6(APC):c.647G>A(p.Arg216Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,606,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

APC
NM_000038.6 missense, splice_region

Scores

Splicing: ADA: 0.0004482

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:3

Conservation

PhyloP100: 0.880

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06739414).

BP6

Variant 5-112792447-G-A is Benign according to our data. Variant chr5-112792447-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188275.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3}.

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6 linkuse as main transcript	c.647G>A	p.Arg216Gln	missense_variant, splice_region_variant	7/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.647G>A	p.Arg216Gln	missense_variant, splice_region_variant	7/16	5	NM_000038.6	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250290

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135280

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000657

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1454642

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

723576

show subpopulations

Gnomad4 AFR exome

AF:

0.000450

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000461

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the APC protein (p.Arg216Gln). This variant is present in population databases (rs76685252, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer (PMID: 18199528, 28135145, 35264596). ClinVar contains an entry for this variant (Variation ID: 188275). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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	Myriad Genetics, Inc.	Feb 15, 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	Counsyl	Jun 06, 2017	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer or adenomas (Azzopardi et al., 2008; Minde et al., 2011; Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 21859464, 28748566, 28873162, 27329244, 18199528, 26332594, 28135145) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 05, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 29, 2024	The p.R216Q variant (also known as c.647G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in a cohort of 691 North Americans, in one individual with 11-99 colorectal adenomas (Azzopardi D et al. Cancer Res. 2008 Jan;68:358-63), and has also been reported in a cohort of individuals with unselected colorectal cancer (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). This amino acid position is not well conserved in available vertebrate species. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 02, 2024

Variant summary: APC c.647G>A (p.Arg216Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 250290 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in APC causing Familial Adenomatous Polyposis (4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.647G>A has been reported in the literature in individuals affected with colorectal cancer and breast cancer (examples:Azzopardi_2008, Yurgelun_2017, Guindalini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18199528, 35264596, 21859464, 36243179, 26332594, 28135145). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS n=7, likely benign n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

APC-Associated Polyposis Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Uncertain

-0.020

Cadd

Uncertain

Dann

Benign

0.96

DEOGEN2

Benign

0.40

T;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.012

FATHMM_MKL

Benign

0.71

M_CAP

Benign

0.056

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.69

N;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

0.16

N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.49

P;P;.

Vest4

0.31

MVP

0.96

ClinPred

0.050

GERP RS

3.1

Varity_R

0.060

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00045

dbscSNV1_RF

Benign

0.076

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