Submissions for variant NM_000038.6(APC):c.6724A>G (p.Ser2242Gly)

gnomAD frequency: 0.00008  dbSNP: rs201375478

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034395	SCV000149023	uncertain significance	not provided	2018-10-09	criteria provided, single submitter	clinical testing	This variant is denoted APC c.6724A>G at the cDNA level, p.Ser2242Gly (S2242G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant was observed in at least one individual with colon cancer and in a patient with breast cancer (Tung 2015, Yurgelun 2015, Yurgelun 2017). APC Ser2242Gly was observed at an allele frequency of 0.025% (31/126386) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the basic domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ser2242Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115114	SCV000183843	likely benign	Hereditary cancer-predisposing syndrome	2019-11-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987580	SCV000254030	benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000034395	SCV000333806	uncertain significance	not provided	2015-09-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034395	SCV000600137	benign	not provided	2021-03-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515374	SCV000611340	uncertain significance	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115114	SCV000681821	likely benign	Hereditary cancer-predisposing syndrome	2020-06-09	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000664301	SCV000788230	likely benign	Familial multiple polyposis syndrome	2018-04-01	criteria provided, single submitter	research	The APC variant designated as NM_000038.5:c.6724A>G (p.Ser2242Gly) is classified as likely benign. This variant was observed or imputed to be present in two individuals in the same family that are over seventy years old without colorectal cancer, one of whom was documented to not have polyps on colonoscopy. These observations are not consistent with either attenuated or classic familial adenomatous polyposis syndromes. This variant is in ExAC (rs201375478) and is present in approximately 1/3355 individuals of European ancestry, which is greater than the incidence of familial adenomatous polyposis (1/8,000 to 1/10,000). This genomic position is conserved. This variant was also found in co-occurrence with an MSH2 pathogenic mutation. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Mendelics	RCV000987580	SCV001136938	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001151801	SCV001312971	likely benign	APC-Associated Polyposis Disorders	2017-11-02	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211930	SCV001339031	benign	not specified	2021-04-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.6724A>G (p.Ser2242Gly) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250838 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.0 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.6724A>G has been reported in the literature in individuals affected with ovarian carcinoma, breast cancer and colorectal cancer (Kanchi_2014, tung_2014, Yurgelun_2015, Yurgelun_2017, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least two co-occurrences with other pathogenic variants have been reported (BRCA2 c.9294C>G, p.Tyr3098Ter; BRCA1 c.5329dupC, p.Gln1777ProfsTer74), providing supporting evidence for a benign role (Tung-2014, Zhunussova_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments citing overlapping evidence utilized in the context of this evaluation (benign, n=1; likely benign, n=4, VUS, n=6). At-least two submitters have re-classified this variant into a benign/likely benign outcome since our previous evaluation. Based on the evidence outlined above, the variant was classified as benign.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000987580	SCV001429678	likely benign	Familial adenomatous polyposis 1	2019-02-13	criteria provided, single submitter	clinical testing	Data included in classification: The variant was observed in 33/141,114 gnomAD controls. (BS1_strong). Missense variant in a gene for which primarily truncating variants are known to cause disease (BP1_sup). Data not included in classification: UK Family 1: Variant found in 2 year old with Gardner fibroma from Finland and his healthy father. In silico tools mixed predictions. Listed on LOVD3 in combination with 2709_2712delCAGA frameshift variant (phase unknown). Multiple recent classifications of variant by US labs as VUS and likely benign.
Sema4, Sema4	RCV000115114	SCV002534452	likely benign	Hereditary cancer-predisposing syndrome	2021-04-11	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034395	SCV003799786	likely benign	not provided	2022-06-24	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211930	SCV004025083	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034395	SCV000043134	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	RCV001353961	SCV000591200	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ser2242Gly variant has not been previously identified in the literature or by our laboratory. The Ser2242 residue is conserved in mammals, however, computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. Splicing prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a novel splice site in 4 out of 5 different programs, increasing the likelihood that this variant may have a functional consequence, however, this information is not predictive enough to determine outcome and functional studies would be necessary to prove causality. In summary, based on the information above, the clinical significance of this variant cannot be determined with certainty at this time. Therefore, this variant is classified as VUS.
PreventionGenetics, part of Exact Sciences	RCV003944874	SCV004775577	uncertain significance	APC-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The APC c.6724A>G variant is predicted to result in the amino acid substitution p.Ser2242Gly. This variant was reported in individuals with colorectal or breast cancer (see, for example, Yurgelun et al. 2015. PubMed ID: 25980754; Yurgelun et al. 2017. PubMed ID: 28135145; Rizzolo et al. 2019. PubMed ID: 30613976; Zhunussova et al. 2019. PubMed ID: 3148572, supplementary data; Tung et al. 2015. PubMed ID: 25186627, supplementary data). This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41510/). This variant was also described in an individual who already harbored a known causative variant in MSH2 (Tsai et al. 2019. PubMed ID: 30374176). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.