ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3249T>G (p.Asp1083Glu) (rs201629780)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129075 SCV000183778 benign Hereditary cancer-predisposing syndrome 2015-11-27 criteria provided, single submitter clinical testing This alteration is classified as 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.
Invitae RCV001080075 SCV000261248 benign Familial adenomatous polyposis 1 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000034410 SCV000292453 likely benign not provided 2021-02-03 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; This variant is associated with the following publications: (PMID: 25722345, 25203624, 22703879, 24599579, 12093899, 28051113, 27882345, 7562975)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034410 SCV000694028 benign not provided 2016-05-16 criteria provided, single submitter clinical testing Variant summary: The APC c.3249T>G (p.Asp1083Glu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). It does not lie in a known MCR (mutation cluster region) located at exon 15 where pathogenic variants are clustered (PMIDs 1338904 and 18387968). This variant was found in 17/121710 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0002413 (16/66310). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In a FAP family reported in literature, it was found in affected as well as unaffected members suggesting that it is unlikely to cause disease in the family (Gayther_1995). In addition, it was also found to co-occur with another pathogenic variant c.1312+3A>G in one sample reported n UMD database, further supporting a benign outcome. A diagnostic center and a reputable database have classified this variant as likely benign/benign. Taken together, this variant has been classified as Benign.
PreventionGenetics,PreventionGenetics RCV000034410 SCV000805391 likely benign not provided 2017-05-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034410 SCV000887519 benign not provided 2018-02-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129075 SCV000910614 benign Hereditary cancer-predisposing syndrome 2016-06-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001253953 SCV001429837 likely benign APC-Associated Polyposis Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034410 SCV000043119 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000034410 SCV000591136 likely benign not provided no assertion criteria provided clinical testing The APC p.Asp1083Glu variant has been previously reported in the literature in the rectum/sigmoid colon tumour of a 77-year-old colorectal cancer patient, in addition to another pathogenic APC variant; however, it is not clear if these variants were on the same or opposite alleles (Smith 2002). The p.Asp1083Glu variant was also listed in the Exome Variant Server in 3/13001 chromosomes of apparently healthy individuals. This residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign.

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