ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1139G>A (p.Arg380Gln) (rs587782886)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132523 SCV000187620 likely benign Hereditary cancer-predisposing syndrome 2017-07-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene,Other data supporting benign classification
GeneDx RCV000586652 SCV000209488 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing This variant is denoted APC c.1139G>A at the cDNA level, p.Arg380Gln (R380Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been identified in at least one individual undergoing APC genetic testing in a commercial laboratory and another with familial colorectal cancer (Kerr 2013, Hansen 2017). APC Arg380Gln was observed at an allele frequency of 0.024% (3/11,490) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg380Gln occurs at a position that is conserved across species and is not located within a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Arg380Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000586652 SCV000219132 benign not provided 2019-02-13 criteria provided, single submitter clinical testing
Color RCV000132523 SCV000681444 likely benign Hereditary cancer-predisposing syndrome 2018-02-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000722127 SCV000693989 likely benign not specified 2018-06-08 criteria provided, single submitter clinical testing Variant summary: APC c.1139G>A (p.Arg380Gln) results in a conservative amino acid change located in one of the N-terminal Armadillo repeats of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 276480 control chromosomes. The observed variant frequency in gnomAD is slightly above the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). In addition, the frequency of the variant in the Latino subpopulation is greater than 4 fold above the maximal expected allele frequency (2.9e-04 vs 7.1e-05), suggesting that the variant is benign. The variant has been previously reported to co-occur with another pathogenic APC mutation in trans, further supporting a benign outcome for the variant. c.1139G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis without strong evidence for pathogenicity (e.g., cosgregation data). Thus, these reports do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 conflicting interpretations, including VUS (2x), likely benign (1x) and benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000586652 SCV000805363 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing
Mendelics RCV000168435 SCV000838073 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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