Submissions for variant NM_000251.2(MSH2):c.2458+1G>A (rs267608010)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076478	SCV000107507	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
GeneDx	RCV000479442	SCV000567757	pathogenic	not provided	2015-08-28	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.2458+1G>A or IVS14+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 14 of the MSH2 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one individual with a suggestive history of Lynch syndrome (Mangold 2005). we consider this variant to be pathogenic.
Ambry Genetics	RCV000491889	SCV000580590	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-25	criteria provided, single submitter	clinical testing	The c.2458+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the MSH2 gene. This mutation was previously identified in one individual whose personal and/or family history was suggestive of HNPCC (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702). This pathogenic mutation has also been identified in several families meeting Amsterdam criteria for HNPCC/Lynch syndrome with absent MSH2 staining on immunohistochemistry (IHC) (Ambry internal data). 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 a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479442	SCV000601466	likely pathogenic	not provided	2017-04-13	criteria provided, single submitter	clinical testing
Invitae	RCV000704889	SCV000833861	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-11-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the MSH2 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 reported in an individual affected with suspected Lynch syndrome (PMID: 15849733). ClinVar contains an entry for this variant (Variation ID: 90976). Donor and acceptor splice site variants 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). 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.
Color Health, Inc	RCV000491889	SCV000908329	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-01	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 14 of the MSH2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual with personal and/or family history of Lynch syndrome-associated cancers (PMID: 15849733). 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 Likely Pathogenic.