rs777603154
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
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
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
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: 10AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251158Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135762
GnomAD4 exome AF: 0.0000781 AC: 114AN: 1459866Hom.: 0 Cov.: 29 AF XY: 0.0000730 AC XY: 53AN XY: 726354
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74348
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign: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:1Benign: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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at