rs777603154

Positions:

• chr5-112792521-G-A
• chr5-112792521-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000038.6(APC):​c.721G>A​(p.Glu241Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000769 in 1,612,054 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). Synonymous variant affecting the same amino acid position (i.e. E241E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 7.00

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26392078).
• BP6: Variant 5-112792521-G-A is Benign according to our data. Variant chr5-112792521-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 243106.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.721G>A	p.Glu241Lys	missense_variant	7/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.721G>A	p.Glu241Lys	missense_variant	7/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251158 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135762

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: 0.000924

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.0000781 AC: 114 AN: 1459866 Hom.: 0 Cov.: 29 AF XY: 0.0000730 AC XY: 53 AN XY: 726354

Gnomad4 AFR exome AF: 0.0000299

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: 0.000901

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2018	Variant summary: APC c.721G>A (p.Glu241Lys) 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. 5/5 computational tools predict no significant impact on normal splicing, which has been confirmed by a minigene assay (Dominguez-Valentin_2018). The variant allele was found at a frequency of 0.00015 in 277086 control chromosomes. The observed variant frequency is approximately 2.0 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 benign. c.721G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis or other types of cancer. At-least one recent publication classified this variant as probably benign (Zhang_2015). Another publication reported its presence in a patient diagnosed with congenital erythropoietic porphyria (CEP) by biochemical testing and confirmed DNA analysis showing homozygosity for the UROS C73R mutation, which is known to cause a severe phenotype (Wang_2015). This supports its presence in the setting of an alternate molecular basis of disease supporting a benign role for this variant in that setting. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 14, 2018	The APC c.721G>A; p.Glu241Lys variant (rs777603154) is reported in the literature in individuals affected with familial adenomatous polyposis, hereditary colorectal cancer, or breast or gynecological cancer (Dominguez-Valentin 2018, Kanter-Smoler 2006, Zhou 2004). However, this variant was not reported to cosegregate with disease in one family (Zhou 2004), and it co-occurred with a homozygous pathogenic MUTYH p.Pro405Leu variant in affected individuals of another family (Kanter-Smoler 2006). The APC p.Glu241Lys variant is reported in ClinVar (Variation ID: 243106) and is found in the Finnish European population with an overall allele frequency of 0.08% (20/25776 alleles) in the Genome Aggregation Database. The glutamate at codon 241 is highly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Unlike the p.Glu241Lys variant, the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). However, given the lack of clinical and functional data, the significance of the p.Glu241Lys variant is uncertain at this time. References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. Dominguez-Valentin M et al. Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds. Hered Cancer Clin Pract. 2018 Jan 15;16:4. Kanter-Smoler G et al. Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization. Clin Gastroenterol Hepatol. 2006 Apr;4(4):499-506. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Zhou XL et al. Definition of candidate low risk APC alleles in a Swedish population. Int J Cancer. 2004 Jul 1;110(4):550-7. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 31, 2022	This missense variant replaces glutamic acid with lysine at codon 241 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 and a minigene splicing assay observed normal splicing with the variant (PMID: 29371908). To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 15122587). This variant has been identified in 42/282530 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. -

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

Nov 30, 2023

This missense variant replaces glutamic acid with lysine at codon 241 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 and a minigene splicing assay observed normal splicing with the variant (PMID: 29371908). To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 15122587). This variant has been identified in 42/282530 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2017

This variant is denoted APC c.721G>A at the cDNA level and p.Glu241Lys (E241K) at the protein level, and results in the change of a Glutamic acid to a Lysine (GAA>AAA). This variant, published as APC c.739G>A using alternate nomenclature, reportedly did not segregate with disease in a hereditary colorectal cancer kindred and was also seen in individuals with sporadic colorectal cancer and population-based controls (Zhou 2004). APC Glu241Lys was also identified in siblings with adenomatous polyposis who also harbored biallelic MUTYH pathogenic variants (Kanter-Smoler 2006) and in at least one individual referred for hereditary cancer testing (Yorcyzk 2014). APC Glu241Lys was observed at an allele frequency of 0.08% (20/25776) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Glutamic acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Glu241Lys occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Glu241Lys is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Familial adenomatous polyposis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.033	D;D;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.73	P;P;.
Vest4		0.80
MVP		0.95
ClinPred		0.092	T
GERP RS		5.1
Varity_R		0.20
gMVP		0.43

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: rs777603154; hg19: chr5-112128218;