Submissions for variant NM_000179.3(MSH6):c.2665C>T (p.Gln889Ter)

dbSNP: rs1558666177

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneKor MSA	RCV000708612	SCV000821739	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Glutamine to a premature translational stop signal at codon 889 of the MSH6 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in the MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant has been described in the international literature in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747).
Ambry Genetics	RCV000708612	SCV002744143	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	The p.Q889* pathogenic mutation (also known as c.2665C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2665. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis et al. BMC Cancer 2019 Jun;19(1):535). 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.
Myriad Genetics, Inc.	RCV003453510	SCV004188247	pathogenic	Lynch syndrome 5	2023-08-17	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.
Invitae	RCV003758910	SCV004536951	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln889*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 584468). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003999789	SCV004838449	pathogenic	Lynch syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 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.