ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8261G>A (p.Ser2754Asn) (rs369721828)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590250 SCV000149037 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing This variant is denoted APC c.8261G>A at the cDNA level, p.Ser2754Asn (S2754N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant was observed in at least one individual with early-onset colorectal cancer, and 1/128 unaffected Ashkenazi Jewish controls who underwent whole genome sequencing (Carmi 2014, Pearlman 2016). APC Ser2754Asn was observed at an allele frequency of 0.158% (16/10,136) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. APC Ser2754Asn occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in the EB1 binding 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 Ser2754Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115128 SCV000185823 benign Hereditary cancer-predisposing syndrome 2015-08-03 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Insufficient or conflicting evidence
Invitae RCV000197863 SCV000254046 likely benign Familial adenomatous polyposis 1 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000197863 SCV000488248 uncertain significance Familial adenomatous polyposis 1 2016-02-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000722129 SCV000694140 likely benign not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The APC c.8261G>A (p.Ser2754Asn) variant located in the EB-1 binding domain (InterPro) involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 21/276830 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.001579 (16/10136). This frequency is about 22 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in Ashkenazi Jewish individuals. A publication, Pearlman_2017, cites the variant in a female diagnosed with colorectal cancer, however, limited information is provided (ie, lack of cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "uncertain significance" or "benign." Taken together, this variant is classified as likely benign.
Color Health, Inc RCV000115128 SCV000910685 likely benign Hereditary cancer-predisposing syndrome 2016-03-23 criteria provided, single submitter clinical testing

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