Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color | RCV000775368 | SCV000909676 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-09-21 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000663281 | SCV000786518 | pathogenic | Hereditary nonpolyposis colorectal cancer type 4 | 2018-05-17 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000469599 | SCV000551954 | likely pathogenic | Hereditary nonpolyposis colon cancer | 2018-11-30 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 5 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs758304323, ExAC 0.009%). This variant has been observed in individuals affected with Lynch syndrome (PMID: 28449805, 28640387). ClinVar contains an entry for this variant (Variation ID: 411028). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). 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. |
| Laboratory for Molecular Medicine, |
RCV000825602 | SCV000966945 | likely pathogenic | Lynch syndrome | 2017-12-27 | criteria provided, single submitter | clinical testing | The c.538-2A>G variant in PMS2 has been reported in at least 1 Hispanic individu al with PMS2-associated cancer and absence of PMS2 staining via IHC in their tum or sample (Sunga 2017, Ricker 2017). It has also been identified in 3/33582 of L atino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org/; dbSNP rs758304323). This frequency is low enough to be consiste nt with the frequency of Lynch syndrome in the general population. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. A nother variant (c.538-3C>G) impacting the same splice region was shown to result in two aberrant RNA transcripts (in-frame skipping of exon 6 and a 49-bp deleti on producing a frameshift) in an affected carrier (Borras 2013). Furthermore, a large deletion resulting in the in-frame loss of exon 6 was classified as pathog enic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108368.2). In summary, although additional studies are required to fully e stablish its clinical significance, the c.538-2A>G variant is likely pathogenic. ACMG/AMP Criteria applied: PM4, PM5, PP3, PP4. |