ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7625A>G (p.Asn2542Ser) (rs151163793)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122802 SCV000166059 uncertain significance Familial adenomatous polyposis 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2542 of the APC protein (p.Asn2542Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs151163793, ExAC 0.04%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 135719). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000766452 SCV000292466 uncertain significance not provided 2017-03-21 criteria provided, single submitter clinical testing This variant is denoted APC c.7625A>G at the cDNA level, p.Asn2542Ser (N2542S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been reported in at least one pediatric patient with leukemia (Zhang 2015). APC Asn2542Ser was observed at an allele frequency of 0.038% (4/10,398 alleles) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. APC Asn2542Ser occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Asn2542Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000122802 SCV000488366 uncertain significance Familial adenomatous polyposis 1 2016-03-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235882 SCV000600157 uncertain significance not specified 2016-11-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575243 SCV000667284 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000575243 SCV000903019 likely benign Hereditary cancer-predisposing syndrome 2016-03-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235882 SCV000918429 uncertain significance not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: APC c.7625A>G (p.Asn2542Ser) results in a conservative amino acid change located in the Adenomatous polyposis coli protein basic 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 5.4e-05 in 276408 control chromosomes, predominantly at a frequency of 0.00058 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 8-folds higher than 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 African origin. c.7625A>G has been reported in the literature in individuals affected with Colorectal cancer and subtype B-Lineage ALL E2A-PBX1 (Zheng_2015, Yurgelun_2017). These two 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. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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