Submissions for variant NM_000251.3(MSH2):c.1827del (p.His610fs)

dbSNP: rs587779112

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076297	SCV000107318	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000491249	SCV000580540	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-11	criteria provided, single submitter	clinical testing	The c.1827delT pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1827, causing a translational frameshift with a predicted alternate stop codon (p.H610Tfs*25). 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	RCV000531842	SCV000625320	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-01	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MSH2-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90796). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His610Thrfs*25) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323385	SCV000917695	pathogenic	Hereditary nonpolyposis colon cancer	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1827delT (p.His610ThrfsX25) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251474 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1827delT in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491249	SCV001357029	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 12 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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.
Myriad Genetics, Inc.	RCV003452859	SCV004187915	pathogenic	Lynch syndrome 1	2023-08-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.