Submissions for variant NM_000179.3(MSH6):c.461C>G (p.Ser154Ter)

dbSNP: rs1553411391

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629824	SCV000750780	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-06-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 525662). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser154*) 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).
Color Diagnostics, LLC DBA Color Health	RCV001805232	SCV002052065	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 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). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001805232	SCV002636597	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-19	criteria provided, single submitter	clinical testing	The p.S154* pathogenic mutation (also known as c.461C>G), located in coding exon 3 of the MSH6 gene, results from a C to G substitution at nucleotide position 461. This changes the amino acid from a serine to a stop codon within coding exon 3. 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.	RCV003451488	SCV004185720	pathogenic	Lynch syndrome 5	2023-08-10	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.