Submissions for variant NM_000179.3(MSH6):c.1921G>T (p.Glu641Ter)

dbSNP: rs1553413305

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657743	SCV000779495	pathogenic	not provided	2018-06-21	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1921G>T at the cDNA level and p.Glu641Ter (E641X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Ambry Genetics	RCV001013705	SCV001174326	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	The p.E641* pathogenic mutation (also known as c.1921G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 1921. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386205	SCV001586344	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu641*) 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: 546003). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451608	SCV004185837	pathogenic	Lynch syndrome 5	2023-08-16	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.