Submissions for variant NM_000251.3(MSH2):c.1386+2T>C

dbSNP: rs1675076969

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001186193	SCV001352544	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-06	criteria provided, single submitter	clinical testing	This variant causes a T>C nucleotide substitution at the +2 position of intron 8 of the MSH2 gene. Splice site prediction tools predict 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 not been reported in individuals affected with hereditary cancer in the literature. 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 Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284006	SCV001469551	pathogenic	not provided	2020-02-26	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Ambry Genetics	RCV001186193	SCV002702602	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-19	criteria provided, single submitter	clinical testing	The c.1386+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 8 in the MSH2 gene. This alteration was reported in two different Asian probands whose Lynch syndrome associated tumors demonstrated loss of both MSH2/MSH6 protein expression on immunohistochemistry (IHC) (Lee J et al. BMC Cancer, 2017 12;17:843; Tian W et al. Int. J. Cancer, 2019 09;145:1290-1298). This alteration was identified in the germline of an individual whose colon tumor demonstrated high microsatellite instability (MSI-H) and loss of MSH2 protein expression on IHC (Ambry internal data). This alteration was also identified as somatic in a MSI-H endometrial tumor that displayed loss of both MSH2 and MSH6 on IHC and a second somatic pathogenic mutation in MSH2 was identified (Ambry internal data). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice donor site; however direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data reported 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.
Myriad Genetics, Inc.	RCV003449606	SCV004186608	likely pathogenic	Lynch syndrome 1	2023-08-01	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.