Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV003315546 | SCV000253998 | uncertain significance | Familial adenomatous polyposis 1 | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 766 of the APC protein (p.Ala766Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 41522). 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. |
Gene |
RCV000034407 | SCV000292451 | uncertain significance | not provided | 2022-08-18 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals undergoing exome sequencing (Johnston et al., 2012); This variant is associated with the following publications: (PMID: 18199528, 22703879) |
Counsyl | RCV000199077 | SCV000489345 | uncertain significance | Familial adenomatous polyposis 1 | 2016-09-21 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000562498 | SCV000667287 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-01 | criteria provided, single submitter | clinical testing | The p.A766V variant (also known as c.2297C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2297. The alanine at codon 766 is replaced by valine, an amino acid with similar properties. This variant was detected as a secondary finding in 1 out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am. J. Hum. Genet., 2012 Jul;91:97-108). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Color Diagnostics, |
RCV000562498 | SCV000681515 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-22 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with valine at codon 766 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 4/282134 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. |
Preventiongenetics, |
RCV000034407 | SCV000805379 | uncertain significance | not provided | 2018-01-02 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000779709 | SCV000916464 | uncertain significance | not specified | 2023-06-26 | criteria provided, single submitter | clinical testing | Variant summary: APC c.2297C>T (p.Ala766Val) results in a non-conservative amino acid change in 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 1.2e-05 in 251872 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2297C>T has been reported in the literature in at least one individual affected with a Peutz-Jeghers phenotype without evidence of causality (example: Gaddam et al., Am J Gastroenterology 113():p S956, 2018). These report(s) 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. The following publications have been ascertained in the context of this evaluation (Gaddam_2018; PMID: 22703879). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
St. |
RCV000199077 | SCV002032311 | uncertain significance | Familial adenomatous polyposis 1 | 2022-08-10 | criteria provided, single submitter | clinical testing | The APC c.2297C>T (p.Ala766Val) missense change has a maximum subpopulation frequency of 0.0040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with APC-related familial adenomatous polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
Sema4, |
RCV000562498 | SCV002527076 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-01 | criteria provided, single submitter | curation | |
Myriad Genetics, |
RCV003315546 | SCV004018798 | uncertain significance | Familial adenomatous polyposis 1 | 2023-02-22 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
Baylor Genetics | RCV000199077 | SCV004208945 | uncertain significance | Familial adenomatous polyposis 1 | 2023-08-30 | criteria provided, single submitter | clinical testing | |
Biesecker Lab/Clinical Genomics Section, |
RCV000034407 | SCV000043114 | variant of unknown significance | not provided | 2012-07-13 | no assertion criteria provided | research | Converted during submission to Uncertain significance. |