Submissions for variant NM_000251.3(MSH2):c.646-2A>G

dbSNP: rs587779169

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076665	SCV000107707	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000817666	SCV000958243	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-20	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the MSH2 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 MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 12624141, 21642682, 26517685, 29758216). This variant is also known as IVS3-2A>G. ClinVar contains an entry for this variant (Variation ID: 91161). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800376	SCV002046652	pathogenic	not provided	2021-02-13	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-acceptor site and interferes with normal MSH2 mRNA splicing. The variant has been reported in individuals affected with Lynch Syndrome and endometrial cancer in the published literature (PMIDs: 26517685 (2015), 21642682 (2011), and 12624141 (2003)). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV002362714	SCV002660709	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-24	criteria provided, single submitter	clinical testing	The c.646-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 4 in the MSH2 gene. This alteration has been identified in HNPCC/Lynch syndrome families and one proband had an endometrial tumor that demonstrated microsatellite instability (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Jóri B et al. Oncotarget, 2015 Dec;6:41108-22). This alteration has also been identified in a proband whose family history met Amsterdam I/II criteria for Lynch syndrome and a relative had tumor testing that demonstrated loss of MSH2, MSH6 staining on immunohistochemistry (IHC) (Ambry internal data). In addition, this alteration was identified as somatic in conjunction with a second somatic pathogenic MSH2 variant in a MSI-H colorectal tumor that demonstrated loss of both MSH2/MSH6 on IHC (Ambry internal data). Another alteration impacting the same acceptor site (c.646-1G>C) has been detected in a proband who met Amsterdam II criteria for Lynch syndrome and had tumor testing that demonstrated loss of MSH2, MSH6 staining on IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (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 a disease-causing mutation.
GeneDx	RCV001800376	SCV003806055	likely pathogenic	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Parc et al., 2003; Bonadona et al., 2011; Jori et al., 2015; Ten Broeke et al., 2018); This variant is associated with the following publications: (PMID: 18822302, 21120944, 12624141, 21642682, 26517685, 29758216)
Myriad Genetics, Inc.	RCV003452957	SCV004186713	likely pathogenic	Lynch syndrome 1	2023-07-27	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	RCV003452957	SCV004196906	likely pathogenic	Lynch syndrome 1	2022-05-20	criteria provided, single submitter	clinical testing