Submissions for variant NM_000251.3(MSH2):c.2335dup (p.Met779fs)

dbSNP: rs63750149

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076459	SCV000107488	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000490902	SCV000580605	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	clinical testing	The c.2335dupA pathogenic mutation, located in coding exon 14 of the MSH2 gene, results from a duplication of A at nucleotide position 2335, causing a translational frameshift with a predicted alternate stop codon (p.M779Nfs*8). This mutation has been reported in a patient meeting Amsterdam criteria for HNPCC (Lin X et al. Dig. Dis. Sci. 1999 Mar;44:553-9). In addition to the clinical data presented in the literature, 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	RCV000697514	SCV000826130	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-05-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been observed in an individual affected with Lynch syndrome (PMID: 10080150). This variant is also known as a single base insertion ATG XAATG, in the literature. ClinVar contains an entry for this variant (Variation ID: 90957). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met779Asnfs*8) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076459	SCV000917710	likely pathogenic	Lynch syndrome	2018-04-26	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2335dupA (p.Met779AsnfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (eg. c.2460_2462delinsA (p.Val821fsX2), c.2466T>A (p.Cys822X), and c.2633_2634delAG (p.Glu878fsX3)). The variant was absent in 246228 control chromosomes (gnomAD). The variant, c.2335dupA, has been reported in the literature in an individual affected with Lynch Syndrome (Lin_1999). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000490902	SCV001359867	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 14 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.	RCV003452906	SCV004186773	pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.