ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8182G>A (p.Val2728Met) (rs587778045)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000679090 SCV000209558 uncertain significance not provided 2015-10-26 criteria provided, single submitter clinical testing This variant is denoted APC c.8182G>A at the cDNA level, p.Val2728Met (V2728M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant was identified in 1/681 healthy individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. APC Val2728Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. APC Val2728Met occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the EB1 binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Val2728Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000459779 SCV000552584 uncertain significance Familial adenomatous polyposis 1 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 2728 of the APC protein (p.Val2728Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs587778045, ExAC 0.001%). This variant has been reported in an individual affected with colorectal and thyroid cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 133536). 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. 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.
PreventionGenetics,PreventionGenetics RCV000679090 SCV000805479 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
Color RCV000771522 SCV000904045 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771522 SCV001189782 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000120046 SCV001337838 uncertain significance not specified 2020-01-23 criteria provided, single submitter clinical testing Variant summary: APC c.8182G>A (p.Val2728Met) results in a conservative amino acid change located in the EB-1 binding domain (IPR009232) of 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 8e-06 in 251348 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8182G>A has been reported in the literature in an individual affected with early-onset colorectal cancer and thyroid cancer and also, an individual with kidney renal papillary cell carcinoma (Pearlman_2017, Yehia_2018). 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. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000120046 SCV000084180 not provided not specified 2013-09-19 no assertion provided reference population

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