Submissions for variant NM_000535.7(PMS2):c.538-2A>G (rs758304323)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469599	SCV000551954	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-10-13	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 with clinical features of Lynch syndrome (PMID: 28449805, 28640387, 31101557, Invitae). 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.
Counsyl	RCV000663281	SCV000786518	pathogenic	Hereditary nonpolyposis colorectal cancer type 4	2018-05-17	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000775368	SCV000909676	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-09-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized 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.
Ambry Genetics	RCV000775368	SCV001185960	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-30	criteria provided, single submitter	clinical testing	The c.538-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the PMS2 gene. This alteration has been observed in at least one individual whose colorectal tumor demonstrated loss of PMS2 expression on immunohistochemistry (IHC) and family history was consistent with Lynch syndrome (Ambry internal data). 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 acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). Another alteration impacting the same acceptor site (c.538-1G>C) has been reported in a child with Constitutional MisMatch Repair Deficiency (CMMRD) syndrome in conjunction with a PMS2 gross deletion mutation (Bakry D et al. Eur J Cancer. 2014 Mar;50(5):987-96). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825602	SCV001338459	likely pathogenic	Lynch syndrome	2020-04-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.538-2A>G 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 1.2e-05 in 251470 control chromosomes (gnomAD). c.538-2A>G has been reported in the literature in individuals affected with Lynch syndrome and colorectal cancer (Sunga_2017, Ricker_2017, Mork_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (3x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001576762	SCV001804014	likely pathogenic	not provided	2021-06-10	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in aberrant splicing leading to in-frame loss of the adjacent exon 6, which would disrupt the ATPase domain (Guarne 2001); Observed in individuals with Lynch-associated cancers and tumor studies consistent with pathogenic variants in this gene (Ricker 2017, Mork 2019, Wang 2020); This variant is associated with the following publications: (PMID: 31101557, 28640387, 31992580, 29922827, 27535533, 28449805)