Submissions for variant NM_000251.3(MSH2):c.2789dup (p.Val932fs)

gnomAD frequency: 0.00001  dbSNP: rs786202481

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165311	SCV000216033	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The c.2789dupT variant, located in coding exon 16 of the MSH2 gene, results from a duplication of T at nucleotide position 2789, causing a translational frameshift with a predicted alternate stop codon (p.V932Sfs*21). This alteration occurs at the 3' terminus of the MSH2 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 17 amino acids. This frameshift impacts the last 3amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000198076	SCV000255274	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the MSH2 gene (p.Val932Serfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the MSH2 protein and extend the protein by 17 additional amino acid residues. This variant is present in population databases (rs786202481, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185819). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000236328	SCV000292856	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in the last 3 amino acids being replaced with 20 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with a personal history of breast cancer and family history of breast, ovarian, and gastrointestinal cancers (Bhai et al., 2021); This variant is associated with the following publications: (PMID: 9774676, 18822302, 21120944, 27873144, 34326862)
Color Diagnostics, LLC DBA Color Health	RCV000165311	SCV001358269	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 16 of the MSH2 gene, causing a frameshift in the last exon. This results in a protein product that is 17 amino acids longer than the normal protein product. To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/248670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003468740	SCV004196302	uncertain significance	Lynch syndrome 1	2023-08-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995410	SCV004829986	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 16 of the MSH2 gene, causing a frameshift in the last exon and addition of 20 new amino acids before introducing a stop codon. This results in a protein product that is 17 amino acids longer than the normal 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/248670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.