Submissions for variant NM_000251.3(MSH2):c.2635C>T (p.Gln879Ter)

dbSNP: rs63751469

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076530	SCV000107560	pathogenic	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	This variant is before the cutoff (codon 888) and therefore Class 5
Ambry Genetics	RCV000491055	SCV000580528	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-10	criteria provided, single submitter	clinical testing	The p.Q879* pathogenic mutation (also known as c.2635C>T), located in coding exon 16 of the MSH2 gene, results from a C to T substitution at nucleotide position 2635. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 57 AA of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). In one study, this pathogenic mutation was detected in the germline of an individual referred for Lynch syndrome testing, whose tumor demonstrated high microsatellite instability and loss of protein expression (Baudhin LM et al. J Mol Diagn. 2005 May;7(2):226-35). This variant has also been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry or high microsatellite instability (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000521246	SCV000617595	pathogenic	not provided	2018-03-22	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2635C>T at the cDNA level and p.Gln879Ter (Q879X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA). This variant has been reported in a patient referred for Lynch syndrome testing (Baudhuin 2005). This variant is located in the Helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011, Wielders 2017) and is predicted to cause loss of normal protein function through protein truncation. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 56 amino acids are no longer translated. MSH2 c.2635C>T was not observed in large population cohorts (Lek 2016). Based on currently available evidence, we consider MSH2 c.2635C>T to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697633	SCV000826255	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-05-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln879*) in the MSH2 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with symptoms of Lynch syndrome (PMID: 15858146). This variant is also known as c.2637C>T. ClinVar contains an entry for this variant (Variation ID: 91028). Studies have shown that this premature translational stop signal results in skipping of exon 16 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu888Cysfs*4) have been determined to be pathogenic (PMID: 8640829, 9222765). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000076530	SCV004187999	pathogenic	Lynch syndrome 1	2023-08-09	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.