Submissions for variant NM_000251.3(MSH2):c.212-1G>A

dbSNP: rs267607914

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076394	SCV000107430	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000218216	SCV000278680	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	The c.212-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 2 of the MSH2 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability and/or loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data; Liccardo R et al. Mol Med Rep, 2018 May;17:6942-6946). This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data; Overbeek LI et al. Br J Cancer, 2007 May;96:1605-12; De Lellis L et al. PLoS One, 2013 Nov;8:e81194). 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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000202270	SCV000567721	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in individuals with personal and/or family history of Lynch syndrome-associated cancers (Overbeek et al., 2007; Ramsoekh et al., 2008; De Lellis et al., 2013; Liccardo et al., 2018); This variant is associated with the following publications: (PMID: 17453009, 25525159, 20591884, 24278394, 18625694, 25561518, 28526081, 29568967, 33866195, 33087929, 31615790, 28888541)
Invitae	RCV000696322	SCV000824877	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-01-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of two cryptic splice sites and introduces a premature termination codon (PMID: 29568967). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 90892). Disruption of this splice site has been observed in individuals with Lynch syndrome-associated cancers (PMID: 17453009, 18625694, 20591884, 24278394, 29568967). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Color Diagnostics, LLC DBA Color Health	RCV000218216	SCV001348701	pathogenic	Hereditary cancer-predisposing syndrome	2019-11-13	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the -1 position of intron 1 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Abnormal splicing was observed from the RNA study (PMID: 29568967). This variant has been reported in individuals affected with colorectal cancer (PMID: 17453009, 29568967), Lynch Syndrome or clinical suspicion of Lynch Syndrome (PMID: 18625694, 24278394) and endometrial cancer (PMID: 29345684). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000202270	SCV003916101	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	MSH2: PVS1, PM2, PS4:Moderate
Myriad Genetics, Inc.	RCV003452890	SCV004187937	pathogenic	Lynch syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered 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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003452890	SCV004196898	pathogenic	Lynch syndrome 1	2022-08-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202270	SCV004220976	pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal MSH2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with colon cancer (PMID: 17453009 (2007), 24278394 (2013), 29568967 (2018)) and pituitary macroadenoma (PMID: 33866195 (2021)). RNA analysis has shown that this variant generates two aberrant transcripts with premature termination codons (PMID: 29568967 (2018)). Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076394	SCV004847735	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The c.212-1G>A variant in MSH2 has been reported in 1 individual affected with colorectal cancer (Overbeek 2007), 1 individual with Lynch syndrome (De Lellis 2013), 1 individual with bladder cancer (van der Post 2010), and 1 individual with clinical suspicion of Lynch syndrome (Ramsoekh 2008). It was absent from large population studies. This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 90892). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, the c.212-1G>A variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202270	SCV000257169	pathogenic	not provided		no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250032	SCV001423957	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing