Submissions for variant NM_000038.6(APC):c.3323A>G (p.Asn1108Ser)

gnomAD frequency: 0.00001  dbSNP: rs151286353

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003743632	SCV000261534	likely benign	Familial adenomatous polyposis 1	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000236966	SCV000292731	uncertain significance	not provided	2023-03-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 27930734, 28576136, 28726808, 18199528)
Ambry Genetics	RCV000571447	SCV000667269	likely benign	Hereditary cancer-predisposing syndrome	2018-12-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000571447	SCV000911099	likely benign	Hereditary cancer-predisposing syndrome	2016-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264579	SCV001442802	uncertain significance	not specified	2020-10-15	criteria provided, single submitter	clinical testing	Variant summary: APC c.3323A>G (p.Asn1108Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 281874 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (3.5e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.3323A>G has been reported in the literature in one individual affected with Lynch syndrome-associated cancer and/or colorectal polyps and one individual affected with pancreatic cancer (Yurgelun_2015, Chaffee_2017). 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236966	SCV002011093	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001264579	SCV002071917	uncertain significance	not specified	2021-10-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.3323A>G, in exon 16 that results in an amino acid change, p.Asn1108Ser. This sequence change does not appear to have been previously described in individuals with APC-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.0085% in the Latino/Admixed American subpopulation (dbSNP rs151286353). The p.Asn1108Ser change affects a moderately conserved amino acid residue located in a domain of the APC protein that is not known to be functional. The p.Asn1108Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Asn1108Ser change remains unknown at this time.
Sema4, Sema4	RCV000571447	SCV002533259	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001264579	SCV004243236	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003967554	SCV004788350	uncertain significance	APC-related condition	2023-11-10	criteria provided, single submitter	clinical testing	The APC c.3323A>G variant is predicted to result in the amino acid substitution p.Asn1108Ser. This variant has been reported in an individual undergoing Lynch syndrome clinical genetic testing and in an individual with a personal and family history of pancreatic cancer (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S2, Chaffee et al. 2018. PubMed ID: 28726808). It has also been reported in a control individual from a biliary tract cancer cohort study (Table S2, Okawa et al. 2023. PubMed ID: 36243179). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112174614-A-G). It has conflicting interpretations of likely benign and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/220743/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.