Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000484542 | SCV000565417 | uncertain significance | not provided | 2023-05-08 | criteria provided, single submitter | clinical testing | In-frame deletion of 2 amino acids that are replaced by 2 different amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Reported in an individual undergoing multigene cancer panel testing due to a history of a Lynch-related cancer and/or polyps (Yurgelun et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17016615, 25980754) |
| Fulgent Genetics, |
RCV002489072 | SCV002781286 | uncertain significance | Lynch syndrome 4; Mismatch repair cancer syndrome 4 | 2022-05-17 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002525594 | SCV002999562 | benign | Hereditary nonpolyposis colorectal neoplasms | 2022-06-04 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003114588 | SCV003800810 | uncertain significance | not specified | 2023-01-10 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.1714_1717delinsACAT (p.Ala572_Thr573delinsThrSer) results in an in-frame deletion-insertion that is predicted to delete/insert 2 amino acids from the protein. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. Nevertheless, the constituent variants of this deletion-insertion variant (i.e. c.1714G>A/p.Ala572Thr and c.1717A>T/p.Thr573Ser), are found to co-occur (and are likely part of the same haplotype) in at least some individuals in gnomAD v2.1.1, with the allele frequency being lower than the estimated maximal expected allele frequency for pathogenic variant in PMS2 causing Lynch Syncdrome phenotype (0.00011). However, control population data need to be cautiously considered since the variants lie within a region of the PMS2 gene that has high pseudogene homology. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1714G>A and c.1717A>T have been reported to co-occur in one individual affected with Lynch Syndrome (Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |