Submissions for variant NM_000535.7(PMS2):c.705+1G>A

dbSNP: rs267608147

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001025972	SCV001188264	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	clinical testing	The c.705+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 6 of the PMS2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of PMS2 expression by immunohistochemistry (Ambry internal data).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001025972	SCV001736400	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-12-21	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 6 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. However, two other variants at this splice site, c.702+1G>T and c.705+2T>C, have been observed in an individual affected with PMS2-deficient Lynch syndrome-associated cancer (PMID: 16619239, 18602922) and an individual suspected of constitutional mismatch repair deficiency syndrome (PMID: 23629955), respectively. An RNA study also has shown that c.705+2T>C produced aberrant mRNA transcripts that have in-frame deletions in the ATPase domain (PMID: 23629955). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003455134	SCV004187620	likely pathogenic	Lynch syndrome 4	2023-08-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003758989	SCV004452166	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with colorectal cancer and/or PMS2-related conditions (PMID: 16619239, 23629955; internal data). ClinVar contains an entry for this variant (Variation ID: 826800). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 23629955; internal data). 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.
All of Us Research Program, National Institutes of Health	RCV004807268	SCV005429637	likely pathogenic	Lynch syndrome	2024-08-08	criteria provided, single submitter	clinical testing	The c.705+1G>A variant in the PMS2 gene is located at the canonical splice site of intron 6 and is predicted to inflict donor loss (SpliceAI delta score: 0.89), resulting in alternative splicing and disrupted protein product. Other variants disrupting the same splice region (c.705+2T>C, c.705+1G>T) have been reported in individuals with PMS2-related cancer (PMID: 23629955, 16619239, 18602922), and interpreted as likely pathogenic (ClinVar ID: 920690, 91364). Loss-of-function variants in the PMS2 gene are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant has been reported in ClinVar (ID: 826800). The variant is absent in the general population according to gnomAD (v2.1.1 and v4.1). Therefore, the c.705+1G>A variant in the PMS2 gene has been classified as likely pathogenic.