ClinVar Miner

Submissions for variant NM_000038.6(APC):c.721G>A (p.Glu241Lys) (rs777603154)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236387 SCV000292447 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing 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.
Invitae RCV001082143 SCV000552564 likely benign Familial adenomatous polyposis 1 2020-11-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573590 SCV000667292 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing The p.E241K variant (also known as c.721G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide position 721. The glutamic acid at codon 241 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in 1/91 individuals with hereditary colorectal cancer, 1/94 healthy control individuals and 2/94 individuals with sporadic colorectal cancer from a Swedish cohort (Zhou XL et al. Int. J. Cancer 2004 Jul; 110(4):550-7). It has also been identified in an individual affected with MUTYH-associated polyposis (Kanter-Smoler G et al. Clin. Gastroenterol. Hepatol., 2006 Apr;4:499-506). Another study detected this alteration in a patient with breast or gynecologic cancer with previous negative BRCA1/2 testing, and this study and used a minigene assay to determine that this alteration does not cause a splicing defect (Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2018 Jan;16:4). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000573590 SCV000681856 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-22 criteria provided, single submitter clinical testing 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. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779732 SCV000916498 likely benign not specified 2018-07-09 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000779732 SCV001158686 uncertain significance not specified 2018-08-14 criteria provided, single submitter clinical testing 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.

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