Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000575935 | SCV000668028 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-30 | criteria provided, single submitter | clinical testing | The p.G1679D variant (also known as c.5036G>A), located in coding exon 33 of the ATM gene, results from a G to A substitution at nucleotide position 5036. The glycine at codon 1679 is replaced by aspartic acid, an amino acid with similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Labcorp Genetics |
RCV000792543 | SCV000931847 | uncertain significance | Ataxia-telangiectasia syndrome | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1679 of the ATM protein (p.Gly1679Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 482665). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
Color Diagnostics, |
RCV000575935 | SCV001735585 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-21 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with aspartic acid at codon 1679 of the ATM 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 been reported in an individual affected with pancreatic cancer and a family history of breast and ovarian cancer (PMID: 32885271). This variant has not been identified 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. |
Gene |
RCV004719880 | SCV005326144 | uncertain significance | not provided | 2023-12-22 | criteria provided, single submitter | clinical testing | Observed in an individual with pancreatic cancer (PMID: 32885271); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32885271) |
Department of Pathology and Laboratory Medicine, |
RCV001356167 | SCV001551257 | uncertain significance | Familial pancreatic carcinoma | no assertion criteria provided | clinical testing | The ATM p.Gly1679Asp variant was not identified in the literature nor was it identified in the dbSNP or LOVD 3.0. The variant was identified in ClinVar (classified as uncertain significance by Invitae and Ambry Genetics). The variant was not identified in the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly1679 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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 uncertain significance. |