Submissions for variant NM_000535.7(PMS2):c.904-2A>G (rs587781339)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129110	SCV000183822	pathogenic	Hereditary cancer-predisposing syndrome	2016-09-08	criteria provided, single submitter	clinical testing	The c.904-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the PMS2 gene. This variant was reported in a patient who had right colorectal cancer at age 48, prostate cancer at age 68, and a numerous polyps (Selkirk CG et al. Fam. Cancer. 2014 Dec;13(4):527-36). In addition to the clinical data presented in the literature, 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 pathogenic.
Invitae	RCV000206112	SCV000261727	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-05-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features consistent with Lynch syndrome (PMID: 25117502, 27696107). 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	RCV000576592	SCV000677800	likely pathogenic	Hereditary nonpolyposis colorectal cancer type 4	2017-02-14	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000129110	SCV000686254	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 24763289, 25117502, 27696107, 28514183). 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.