Submissions for variant NM_000038.6(APC):c.835-3T>C

gnomAD frequency: 0.00002  dbSNP: rs372090940

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164509	SCV000215160	likely benign	Hereditary cancer-predisposing syndrome	2019-06-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl	RCV000409101	SCV000487966	uncertain significance	Familial adenomatous polyposis 1	2015-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000432869	SCV000531163	likely benign	not specified	2017-09-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000409101	SCV000552752	likely benign	Familial adenomatous polyposis 1	2022-11-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164509	SCV000911385	benign	Hereditary cancer-predisposing syndrome	2017-04-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000432869	SCV001748700	likely benign	not specified	2021-07-04	criteria provided, single submitter	clinical testing	Variant summary: APC c.835-3T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250968 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.835-3T>C has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with colorectal cancer (example, Yurgelun_2017). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with a majority consensus leaning towards benign (n=1)/likely benign(n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000432869	SCV002071997	uncertain significance	not specified	2021-11-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change in intron 8, c.835-3T>C. This sequence change has been described in the gnomAD database with a frequency of 0.004% in the non-Finnish European subpopulation (dbSNP rs372090940). This sequence change is not predicted to have a deleterious effect on splicing based on in-silico splice prediction programs. This sequence change has been previously described in an individual with colorectal cancer (PMID: 28135145). It is possible that this sequence change represents a benign sequence change in the APC gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.
Myriad Genetics, Inc.	RCV000409101	SCV004017758	likely benign	Familial adenomatous polyposis 1	2023-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001729422	SCV001977774	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001729422	SCV001977994	likely benign	not provided		no assertion criteria provided	clinical testing