Submissions for variant NM_000038.6(APC):c.2593C>T (p.Pro865Ser)

gnomAD frequency: 0.00028  dbSNP: rs192620988

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122764	SCV000166021	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131163	SCV000186108	likely benign	Hereditary cancer-predisposing syndrome	2019-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000587302	SCV000209504	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27124905, 21859464, 14695993, 31159747)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238728	SCV000297018	uncertain significance	Familial multiple polyposis syndrome	2015-09-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000348086	SCV000451998	likely benign	APC-Associated Polyposis Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000122764	SCV000487865	uncertain significance	Familial adenomatous polyposis 1	2015-11-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587302	SCV000600060	likely benign	not provided	2023-02-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228418	SCV000694015	likely benign	not specified	2022-04-09	criteria provided, single submitter	clinical testing	Variant summary: APC c.2593C>T (p.Pro865Ser) results in a non-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. The variant allele was found at a frequency of 8.5e-05 in 282448 control chromosomes. The observed variant frequency is approximately 1.2 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.2593C>T has been reported in the literature in an individual with microsatellite unstable (MSI) sporadic colorectal cancer due to MLH1 promoter hypermethylation and in settings of multigene panel testing of clinical tumor samples (example, Domingo_2004, Goswami_2016). These report(s) 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. Twelve 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/Benign, n=7; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000131163	SCV000821810	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131163	SCV000910647	likely benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Mendelics	RCV003492529	SCV001136895	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587302	SCV001471856	likely benign	not provided	2019-10-08	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587302	SCV002010892	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131163	SCV002538337	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-01	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000587302	SCV002544970	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000122764	SCV003843141	uncertain significance	Familial adenomatous polyposis 1	2022-11-03	criteria provided, single submitter	clinical testing	The APC c.2593C>T (p.Pro865Ser) missense change has a maximum non-founder subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual referred for genetic testing for hereditary cancer predisposition (PMID: 31159747). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131163	SCV004228075	benign	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing