Submissions for variant NM_000038.6(APC):c.6117G>T (p.Leu2039Phe)

gnomAD frequency: 0.00004  dbSNP: rs372418435

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163274	SCV000213802	likely benign	Hereditary cancer-predisposing syndrome	2022-12-01	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	RCV000232978	SCV000282791	uncertain significance	Familial adenomatous polyposis 1	2025-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2039 of the APC protein (p.Leu2039Phe). This variant is present in population databases (rs372418435, gnomAD 0.004%). 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: 184130). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV000656748	SCV000292462	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and polyps (PMID: 34326862); This variant is associated with the following publications: (PMID: 33875564, 25085752, 31175917, 35731023, 34326862, 18199528)
Counsyl	RCV000232978	SCV000489035	uncertain significance	Familial adenomatous polyposis 1	2016-08-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656748	SCV000600123	uncertain significance	not provided	2019-07-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000236184	SCV000602534	uncertain significance	not specified	2017-02-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163274	SCV000681781	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 2039 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 7/282216 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236184	SCV001361153	uncertain significance	not specified	2019-02-14	criteria provided, single submitter	clinical testing	Variant summary: APC c.6117G>T (p.Leu2039Phe) results in a non-conservative amino acid change located in a SAMP motif (IPR009224) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 282216 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 4.7e-05 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is somewhat lower than the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). Therefore the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6117G>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000232978	SCV004018632	likely benign	Familial adenomatous polyposis 1	2023-02-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000232978	SCV004192632	uncertain significance	Familial adenomatous polyposis 1	2024-02-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806124	SCV005426410	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 2039 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 7/282216 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.
Fulgent Genetics, Fulgent Genetics	RCV005042323	SCV005667876	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-04-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353588	SCV000591195	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Leu2039Phe variant was not identified in the literature. The variant was identified in dbSNP (ID: rs372418435) “With uncertain significance allele”, NHLBI Exome Sequencing Project (Exome Variant Server) with a frequency of 0.0001, and the Exome Aggregation Consortium (ExAC) database in 2 of 66680 European (Non-Finnish) chromosomes (frequency: 0.00003). This low number of observations and frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified in the Clinvitae database (classified as uncertain significance) and the ClinVar database (classified as uncertain significance). The p.Leu2039 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV004739510	SCV005356730	uncertain significance	APC-related disorder	2024-09-21	no assertion criteria provided	clinical testing	The APC c.6117G>T variant is predicted to result in the amino acid substitution p.Leu2039Phe. This variant was reported in an individual with breast cancer and in an individual with polyps (Supplementary Table 4, Bhai et al 2021. PubMed ID: 34326862). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/184130/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.