Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000566972 | SCV000670763 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-04-25 | criteria provided, single submitter | clinical testing | The c.803+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 7 in the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was seen in 1/150 unselected patients with recurrent or metastatic prostate cancer (Isaacsson Velho P et al. Prostate, 2018 04;78:401-407). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000566972 | SCV000686241 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-04-05 | criteria provided, single submitter | clinical testing | This variant causes an A to G nucleotide substitution at the +4 position of intron 7 of the PMS2 gene. Splice site prediction tools are inconclusive on whether this variant has a significant impact on RNA splicing. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/248408 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. |
| Gene |
RCV000566972 | SCV000822137 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000818231 | SCV000958832 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-10-05 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756312205, gnomAD 0.0009%). This variant has been observed in individual(s) with prostate cancer and/or personal or family history of hereditary breast and/or ovarian cancer (PMID: 29368341, 31159747). ClinVar contains an entry for this variant (Variation ID: 484256). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Sema4, |
RCV000566972 | SCV002530391 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-03 | criteria provided, single submitter | curation |