chr5-112842318-A-G

Position:

chr5-112842318-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000038.6(APC):c.6724A>G(p.Ser2242Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000998 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:10

Conservation

PhyloP100: 4.68

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40384075).

BP6

Variant 5-112842318-A-G is Benign according to our data. Variant chr5-112842318-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41510.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=3, Uncertain_significance=5}. Variant chr5-112842318-A-G is described in Lovd as [Benign].

BS2

High AC in GnomAd4 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.6724A>G	p.Ser2242Gly	missense_variant	16/16	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.6724A>G	p.Ser2242Gly	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

250838

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135656

show subpopulations

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:

0.000221

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1461634

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	This variant is denoted APC c.6724A>G at the cDNA level, p.Ser2242Gly (S2242G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant was observed in at least one individual with colon cancer and in a patient with breast cancer (Tung 2015, Yurgelun 2015, Yurgelun 2017). APC Ser2242Gly was observed at an allele frequency of 0.025% (31/126386) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the basic domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ser2242Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 24, 2022	- -

Familial adenomatous polyposis 1

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Feb 13, 2019	Data included in classification: The variant was observed in 33/141,114 gnomAD controls. (BS1_strong). Missense variant in a gene for which primarily truncating variants are known to cause disease (BP1_sup). Data not included in classification: UK Family 1: Variant found in 2 year old with Gardner fibroma from Finland and his healthy father. In silico tools mixed predictions. Listed on LOVD3 in combination with 2709_2712delCAGA frameshift variant (phase unknown). Multiple recent classifications of variant by US labs as VUS and likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 14, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2020	- -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2021	Variant summary: APC c.6724A>G (p.Ser2242Gly) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of 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 0.0001 in 250838 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.6724A>G has been reported in the literature in individuals affected with ovarian carcinoma, breast cancer and colorectal cancer (Kanchi_2014, tung_2014, Yurgelun_2015, Yurgelun_2017, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least two co-occurrences with other pathogenic variants have been reported (BRCA2 c.9294C>G, p.Tyr3098Ter; BRCA1 c.5329dupC, p.Gln1777ProfsTer74), providing supporting evidence for a benign role (Tung-2014, Zhunussova_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments citing overlapping evidence utilized in the context of this evaluation (benign, n=1; likely benign, n=4, VUS, n=6). At-least two submitters have re-classified this variant into a benign/likely benign outcome since our previous evaluation. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Carcinoma of colon

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Ser2242Gly variant has not been previously identified in the literature or by our laboratory. The Ser2242 residue is conserved in mammals, however, computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Splicing prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a novel splice site in 4 out of 5 different programs, increasing the likelihood that this variant may have a functional consequence, however, this information is not predictive enough to determine outcome and functional studies would be necessary to prove causality. In summary, based on the information above, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as VUS. -

APC-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2024

The APC c.6724A>G variant is predicted to result in the amino acid substitution p.Ser2242Gly. This variant was reported in individuals with colorectal or breast cancer (see, for example, Yurgelun et al. 2015. PubMed ID: 25980754; Yurgelun et al. 2017. PubMed ID: 28135145; Rizzolo et al. 2019. PubMed ID: 30613976; Zhunussova et al. 2019. PubMed ID: 3148572, supplementary data; Tung et al. 2015. PubMed ID: 25186627, supplementary data). This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41510/). This variant was also described in an individual who already harbored a known causative variant in MSH2 (Tsai et al. 2019. PubMed ID: 30374176). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial multiple polyposis syndrome

Benign:1

Likely benign, criteria provided, single submitter

research

University of Washington Department of Laboratory Medicine, University of Washington

Apr 01, 2018

The APC variant designated as NM_000038.5:c.6724A>G (p.Ser2242Gly) is classified as likely benign. This variant was observed or imputed to be present in two individuals in the same family that are over seventy years old without colorectal cancer, one of whom was documented to not have polyps on colonoscopy. These observations are not consistent with either attenuated or classic familial adenomatous polyposis syndromes. This variant is in ExAC (rs201375478) and is present in approximately 1/3355 individuals of European ancestry, which is greater than the incidence of familial adenomatous polyposis (1/8,000 to 1/10,000). This genomic position is conserved. This variant was also found in co-occurrence with an MSH2 pathogenic mutation. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

APC-Associated Polyposis Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 02, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

.;D

M_CAP

Benign

0.058

MetaRNN

Benign

0.40

T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.89

N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0060

D;D

Sift4G

Benign

0.17

T;T

Polyphen

0.99

D;D

Vest4

0.49

MVP

0.82

ClinPred

0.12

GERP RS

6.0

Varity_R

0.29

gMVP

0.40

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