NM_000251.3:c.2635C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000251.3(MSH2):c.2635C>T(p.Gln879*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000251.3 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:2
This variant is before the cutoff (codon 888) and therefore Class 5 -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
not provided Pathogenic:1
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. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
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. -
Hereditary cancer-predisposing syndrome Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at