Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000218833 | SCV000278208 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-09 | criteria provided, single submitter | clinical testing | The p.C977Y variant (also known as c.2930G>A), located in coding exon 19 of the ATM gene, results from a G to A substitution at nucleotide position 2930. The cysteine at codon 977 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been confirmed in trans with an ATM pathogenic mutation in multiple, related individuals with clinical features of ataxia telangiectasia (external correspondence from GeneDx). In addition, this variant co-segregated with disease in one family tested in an external laboratory. Another alteration at the same codon, p.C977R (c.2929T>C) has been described in an individual diagnosed with ataxia telangiectasia (Galatolo D et al. Int J Mol Sci, 2021 Aug;22(16):8490). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Labcorp Genetics |
RCV000232860 | SCV000282917 | likely pathogenic | Ataxia-telangiectasia syndrome | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 977 of the ATM protein (p.Cys977Tyr). 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 missense change has been observed in individual(s) with ataxia-telangiectasia and/or pancreatic cancer (PMID: 35047863; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 233765). 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. This variant disrupts the p.Cys977 amino acid residue in ATM. Other variant(s) that disrupt this residue have been observed in individuals with ATM-related conditions (PMID: 34445196), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Color Diagnostics, |
RCV000218833 | SCV001348056 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-09 | criteria provided, single submitter | clinical testing | This missense variant replaces cysteine with tyrosine at codon 977 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 performed for this variant. This variant has been reported in the compound heterozygous state in at least one family affected with ataxia-telangiectasia (communication with external laboratories; ClinVar SCV001812983.2, SCV000282917.8). This variant has also been reported in an individual affected with breast cancer (PMID: 31317629). 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 |
RCV001582756 | SCV001812983 | likely pathogenic | not provided | 2023-11-03 | criteria provided, single submitter | clinical testing | Observed in the heterozygous state in individuals breast or pancreatic cancer (PMID: 31317629, 35047863); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31317629, 22895193, 28536309, 19781682, 35047863) |