Description
Variant summary: APC c.6873A>T (p.Gln2291His) results in a non-conservative amino acid change located in the basic domain (IPR009234) of 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 0.00015 in 250976 control chromosomes, predominantly at a frequency of 0.00031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.3-fold 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 Non-Finnish European origin. c.6873A>T has been reported in the literature in individuals affected with colorectal cancer (e.g. Yurgelun_2017), endometrial cancer (e.g. Ring_2016), pancreatic cancer (e.g. Grant_2015), and atherosclerosis (no information regarding cancer history, Johnson_2012). 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. Ten 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, n=6; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
# | Sample | Method | Observation |
---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
---|
1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |