Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001020212 | SCV001181662 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-10-05 | criteria provided, single submitter | clinical testing | The c.3402+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 22 in the ATM gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV001070106 | SCV001235318 | pathogenic | Ataxia-telangiectasia syndrome | 2023-07-17 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 823730). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23 and/or activation of a cryptic splice site in exon 24 and introduces a premature termination codon (PMID: 35245693; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with ATM-related conditions. This sequence change falls in intron 23 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). |
Gene |
RCV003229007 | SCV003926066 | likely pathogenic | not provided | 2022-11-22 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: abnormal splicing resulting in multiple transcripts, including majority out-of-frame skipping of exon 23 as well as minority in-frame transcript (Castillo-Guardiola et al., 2022); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals from one family with breast (DCIS) and colon cancer (Castillo-Guardiola et al., 2022); This variant is associated with the following publications: (PMID: 35245693) |