Submissions for variant NM_000251.3(MSH2):c.2459-12A>G

dbSNP: rs267608012

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160620	SCV000211218	uncertain significance	not provided	2014-09-22	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2459-12A>G or IVS14-12A>G and consists of an A>G nucleotide substitution at the -12 position of intron 14 of the MSH2 gene. Multiple in silico models predict this variant to damage the nearby natural acceptor site, and to possibly cause abnormal gene splicing. This variant was observed in an individual with either a personal or family history suggestive of Lynch syndrome (Mangold 2005). MSH2 c.2459-12A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available information, it is unclear whether MSH2 c.2459-12A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Mendelics	RCV000076479	SCV000837853	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000076479	SCV000887427	likely pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.2459-12A>G has a 98.8% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56, 1.56, 1.56, 1.56, and 26.5 to 1, generated from evidence of seeing this as a somatic mutation in 5 independent tumors 4 of which did not have loss of heterozygosit and one of which had loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV001015604	SCV001176453	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	The c.2459-12A>G intronic variant (also known as IVS14-12A>G) results from an A to G substitution 12 nucleotides upstream from coding exon 15 in the MSH2 gene. This alteration was identified in an individual whose colorectal tumor demonstrated loss of MSH2 protein expression on immunohistochemistry (IHC) and met Amsterdam II criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Ambry internal data). This alteration was also observed in an individual whose colorectal tumor displayed high microsatellite instability (MSI-H) and loss of MSH2 protein expression on IHC (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Mangold E et al. J. Pathol., 2005 Dec;207:385-95). It was subsequently observed in another patient whose HNPCC/Lynch syndrome-related tumor showed loss of MSH2 protein expression on IHC (Barrow, E et al. Histopathology. 2010 Feb;56(3):331-44). This nucleotide position is highly conserved in available primates, but not well conserved in other available vertebrate species. 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 this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358742	SCV001554591	uncertain significance	not specified	2021-03-23	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2459-12A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3 acceptor site. Two predict the variant abolishes a 3 acceptor site. Two predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251254 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2459-12A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and an individual whose colorectal tumor exhibited high microsatellite instability and loss of MSH2 protein expression on IHC (Mangold_2005, Barrow_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001854328	SCV002266540	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-14	criteria provided, single submitter	clinical testing	This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 15849733, 20459533; Invitae). ClinVar contains an entry for this variant (Variation ID: 90977). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein.
Myriad Genetics, Inc.	RCV003452913	SCV004186717	likely pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. 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].
Color Diagnostics, LLC DBA Color Health	RCV001015604	SCV004356743	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -12 position of intron 14 of the MSH2 gene. RNA studies have shown that this variant causes the insertion of 11 nucleotides from intron 14 and disruption of the reading frame, resulting in premature truncation (PMID: 35676339, 36593122). This variant has been reported in more than five individuals affected with Lynch syndrome-associated cancers, with tumors from several individuals showing high microsatellite instability and/or loss of MSH2 protein via immunohistochemistry analysis (PMID: 15849733, 16216036, 20459533, 36457512, 35676339, 36593122). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.