Submissions for variant NM_000038.6(APC):c.8107A>G (p.Lys2703Glu)

gnomAD frequency: 0.00006  dbSNP: rs730881270

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159581	SCV000209557	uncertain significance	not provided	2019-09-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 28873162, 28840378, 29684080)
Illumina Laboratory Services, Illumina	RCV000322812	SCV000452055	uncertain significance	APC-Associated Polyposis Disorders	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000525703	SCV000647753	uncertain significance	Familial adenomatous polyposis 1	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2703 of the APC protein (p.Lys2703Glu). This variant is present in population databases (rs730881270, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 181829). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000575937	SCV000675858	likely benign	Hereditary cancer-predisposing syndrome	2023-03-08	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.
Color Diagnostics, LLC DBA Color Health	RCV000575937	SCV000681911	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 2703 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals with advanced cancer (PMID: 28873162), kidney cancer (PMID: 29684080), and hereditary breast cancer (PMID: 28840378, 29684080). This variant has been identified in 7/282786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000525703	SCV000890941	uncertain significance	Familial adenomatous polyposis 1	2021-08-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000525703	SCV002030091	uncertain significance	Familial adenomatous polyposis 1	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000575937	SCV002531581	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307415	SCV002600455	likely benign	not specified	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: APC c.8107A>G (p.Lys2703Glu) results in a conservative amino acid change located in the EB-1 binding domain of 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 8.2e-05 in 1613976 control chromosomes, predominantly at a frequency of 0.00011 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 1.54 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.8107A>G has been reported in the literature in individuals affected with Cancer (Mendelker_2017, Li_2017, Mito_2018) without strong evidence for causality. 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 (MLH1 c.882C>T), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: seven submitters classified the variant as VUS while two classified the variant as likey benign. Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV000525703	SCV004205231	uncertain significance	Familial adenomatous polyposis 1	2024-01-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998426	SCV004835764	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 2703 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual with advanced cancer (PMID: 28873162), kidney cancer (PMID: 29684080), or hereditary breast cancer (PMID: 28840378, 29684080). This variant has been identified in 7/282786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000525703	SCV001551875	likely benign	Familial adenomatous polyposis 1		no assertion criteria provided	clinical testing	The APC p.Lys2703Glu variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals or families with advanced cancer (unspecified) (Mandelker 2017). The variant was not identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs730881270) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Illumina, Invitae, Ambry Genetics and Color). The variant was identified in control databases in 7 of 277114 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017), observed in the following population: European Non-Finnish in 7 of 126624 chromosomes (freq: 0.00006), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Lys2703 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Glu to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of 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 likely benign.