ClinVar Miner

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

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Total submissions: 5
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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 RCV000461525 SCV000552564 uncertain significance Familial adenomatous polyposis 1 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 241 of the APC protein (p.Glu241Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs777603154, ExAC 0.02%). This variant has been observed in individuals affected with colorectal cancer, breast cancer, and MUTYH-associated colorectal adenomatous polyposis (PMID: 16616356, 15122587, 29371908). ClinVar contains an entry for this variant (Variation ID: 243106). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000573590 SCV000667292 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000573590 SCV000681856 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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