Submissions for variant NM_000251.3(MSH2):c.1840G>T (p.Gly614Ter)

dbSNP: rs1380847972

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001188274	SCV001355296	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 12 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colon cancer whose tumor showed microsatellite instability and loss of MSH2 by immunohistochemistry (PMID: 30693488). 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.
Ambry Genetics	RCV001188274	SCV002717039	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-04	criteria provided, single submitter	clinical testing	The p.G614* pathogenic mutation (also known as c.1840G>T), located in coding exon 12 of the MSH2 gene, results from a G to T substitution at nucleotide position 1840. This changes the amino acid from a glycine to a stop codon within coding exon 12. This mutation has been reported in a 46 year old individual diagnosed with MSI colorectal cancer that exhibited loss of MSH2 and MSH6 proteins on immunohistochemistry (Antelo M et al. Int J Cancer, 2019 08;145:705-713). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV002560014	SCV002966438	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-03-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 925991). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 30693488). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly614*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Myriad Genetics, Inc.	RCV003449614	SCV004186945	pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.