ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs587778045
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Total submissions: 8
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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 RCV002228392 SCV000552584 uncertain significance Familial adenomatous polyposis 1 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2728 of the APC protein (p.Val2728Met). This variant is present in population databases (rs587778045, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer and thyroid cancer (PMID: 27978560, 33821390). ClinVar contains an entry for this variant (Variation ID: 133536). 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.
Preventiongenetics, part of Exact Sciences RCV000679090 SCV000805479 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000771522 SCV000904045 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-27 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 2728 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal and thyroid cancer (PMID: 27978560), and kidney cancer (PMID: 29684080). This variant has also been identified in 2/251348 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.
Ambry Genetics RCV000771522 SCV001189782 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-13 criteria provided, single submitter clinical testing The p.V2728M variant (also known as c.8182G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 8182. The valine at codon 2728 is replaced by methionine, an amino acid with highly similar properties. This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This variant was also identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). In another study, this alteration was detected in an individual diagnosed with papillary thyroid cancer (Mio C et al. Endocrine, 2021 09;73:648-657). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Baylor Genetics RCV003467066 SCV004204541 uncertain significance Familial adenomatous polyposis 1 2023-07-01 criteria provided, single submitter clinical testing
ITMI RCV000120046 SCV000084180 not provided not specified 2013-09-19 no assertion provided reference population

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