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

Total submissions: 10

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.