ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3632T>G (p.Met1211Arg) (rs575268622)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122774 SCV000166031 likely benign Familial adenomatous polyposis 1 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000120048 SCV000569041 uncertain significance not specified 2017-01-26 criteria provided, single submitter clinical testing This variant is denoted APC c.3632T>G at the cDNA level, p.Met1211Arg (M1211R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). While APC Met1211Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project or 1000 Genomes, this variant was identified in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. Since Methionine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Met1211Arg occurs at a position that is not conserved and is not located in a known functional domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Met1211Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120048 SCV000591150 uncertain significance not specified 2014-08-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120048 SCV000600088 uncertain significance not specified 2017-04-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568279 SCV000672492 likely benign Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Counsyl RCV000122774 SCV000784915 uncertain significance Familial adenomatous polyposis 1 2017-02-07 criteria provided, single submitter clinical testing
Color RCV000568279 SCV000902702 likely benign Hereditary cancer-predisposing syndrome 2016-06-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120048 SCV000916513 likely benign not specified 2018-12-07 criteria provided, single submitter clinical testing Variant summary: The variant, APC c.3632T>G (p.Met1211Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 276326 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 30.8 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 South Asian origin. The variant, c.3632T>G has been reported in the literature in individuals affected with breast and colorectal cancer (Chakrabarty_2017, Tung_2015, Chakrabarty _2017). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 (likely benign (2X) and uncertain significance (3X)). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI RCV000120048 SCV000084183 not provided not specified 2013-09-19 no assertion provided reference population

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