ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3875C>T (p.Thr1292Met) (rs371113837)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129039 SCV000172950 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-14 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000198586 SCV000254012 likely benign Familial adenomatous polyposis 1 2019-12-30 criteria provided, single submitter clinical testing
GeneDx RCV000657042 SCV000293018 uncertain significance not provided 2018-08-27 criteria provided, single submitter clinical testing This variant is denoted APC c.3875C>T at the cDNA level, p.Thr1292Met (T1292M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in an individual with colorectal cancer whose father was also diagnosed with late-onset colorectal cancer (Chubb 2015) and in an individual with a clinical diagnosis of FAP; however this variant was reported to not segregate with disease in the family (Nagase 1992). APC Thr1292Met was also identified in at least one individual with breast cancer (Tung 2015) as well as 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the Bodian et al. study were younger than 50 years old thus the unaffected status of this individual may not be significant. APC Thr1292Met was observed at an allele frequency of 0.021% (5/24,030) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in a beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Thr1292Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129039 SCV000681637 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000198586 SCV000803460 uncertain significance Familial adenomatous polyposis 1 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for familial adenomatous polyposis 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657042 SCV000888738 uncertain significance not provided 2018-04-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120026 SCV001361474 uncertain significance not specified 2019-09-23 criteria provided, single submitter clinical testing Variant summary: APC c.3875C>T (p.Thr1292Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 253914 control chromosomes (gnomAD and publications). The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant may be benign. c.3875C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Nagase_1992), Breast Cancer (Tung_2015) or CRC (Chubb_2015, Yurgelun_2017). Nagase_1992 in particular reported the variant within a group of variants that they determined did not cosegregate with FAP phenotype and another mutation that led to translational termination was detected. These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis or other APC-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Institute of Human Genetics, University of Leipzig Medical Center RCV000198586 SCV001429241 uncertain significance Familial adenomatous polyposis 1 2019-12-18 criteria provided, single submitter clinical testing
ITMI RCV000120026 SCV000084157 not provided not specified 2013-09-19 no assertion provided reference population

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