Submissions for variant NM_000535.7(PMS2):c.164-1G>A

gnomAD frequency: 0.00001  dbSNP: rs763308607

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564457	SCV000670751	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-21	criteria provided, single submitter	clinical testing	The c.164-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 3 of the PMS2 gene. This variant has been identified in cis in the literature and likely in cis in our internal cohort with a pathogenic finding in this same gene in multiple individuals with no reported features of constitutional mismatch repair-deficiency, but whose Lynch syndrome-associated tumors demonstrated microsatellite instability and/or loss of PMS2 expression by immunohistochemistry (IHC; Wang Q et al. J Med Genet, 2020 07;57:487-499; Ambry internal data). This alteration was identified in a cohort of individuals suspected of having a hereditary colon cancer syndrome undergoing multigene panel testing (Baert-Desurmont S et al. Eur. J. Hum. Genet. 2018 11;26:1597-1602). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Another alteration impacting the same acceptor site (c.164-1G>C) has been detected in multiple probands whose Lynch syndrome-associated tumors demonstrated loss of PMS2 expression by IHC (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280603	SCV001467816	likely pathogenic	Hereditary nonpolyposis colon cancer	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.164-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 248116 control chromosomes (gnomAD). c.164-1G>A has been reported in the literature in three individuals affected with Colorectal Cancer and found to be associated in cis with the c.137G>T pathogenic variant (p.Ser46Ile) in these three patients (Wang_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378577	SCV001576178	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-08-17	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs763308607, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 484252). 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 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.
Myriad Genetics, Inc.	RCV003451261	SCV004187574	likely pathogenic	Lynch syndrome 4	2023-09-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics	RCV003451261	SCV004205472	likely pathogenic	Lynch syndrome 4	2023-08-27	criteria provided, single submitter	clinical testing
GeneDx	RCV004719882	SCV005326184	likely pathogenic	not provided	2024-01-17	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in cis with another PMS2 pathogenic variant in individuals with colorectal and/or endometrial cancer, with tumors demonstrating microsatellite instability and absent PMS2 staining, in the published literature (PMID: 31992580); This variant is associated with the following publications: (PMID: 29967336, 33309985, 31992580, 29922827)