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 The p.T1292M variant (also known as c.3875C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3875. The threonine at codon 1292 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the literature as an uncertain variant in a 53-year-old male patient with a distal colon cancer and a family history of colon cancer (Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32). Although this alteration (designated 1292 ACG/ATG, Thr/Met) was identified in a patient with familial adenomatous polyposis (FAP), it did not cosegregate with the FAP phenotype in the family and was classified as a polymorphism by the authors (Nagase H et al. Hum. Mutat. 1992;1:467-73). This variant was also reported in a cohort of British cancer patients in an individual with early stage breast cancer (Wong SQ et al. Br. J. Cancer. 2015 Apr;112:1411-20), as well as in a cohort of 681 ancestrally diverse, healthy individuals (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000198586 SCV000254012 likely benign Familial adenomatous polyposis 1 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000657042 SCV000293018 likely benign not provided 2020-09-24 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with colon and other cancers as well as polyps (Nagase 1992, Chubb 2015, Tung 2015, Yurgelun 2017); This variant is associated with the following publications: (PMID: 24728327, 26650777, 25559809, 25742471, 1338764, 27077911, 28135145, 25186627)
Color Health, Inc RCV000129039 SCV000681637 likely benign Hereditary cancer-predisposing syndrome 2020-12-11 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120026 SCV001361474 likely benign not specified 2020-09-29 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 9.5e-05 in 285314 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 1.3 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.3875C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Nagase_1992, Kim_2019), Breast Cancer (Tung_2015) or CRC (Chubb_2015, Yurgelun_2017, Sekine_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. Co-occurrences with other pathogenic variants have been reported (ATM c.2467-1G>A; RNF43 c.1976delG, p.G659fs; APC c.3631_3632del, p.Met1211ValfsTer5) (Internal data, Sekine_2017, Kim_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely 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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