Submissions for variant NM_000179.3(MSH6):c.1933G>T (p.Glu645Ter)

dbSNP: rs1064795591

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483556	SCV000571551	pathogenic	not provided	2020-07-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease Not observed at a significant frequency in large population cohorts (Lek 2016) Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000490938	SCV000580147	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-24	criteria provided, single submitter	clinical testing	The p.E645* pathogenic mutation (also known as c.1933G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 1933. 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	RCV000685973	SCV000813476	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu645*) 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 present in population databases (no rsID available, 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: 422153). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000490938	SCV000910449	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-04	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 been identified in 1/251154 chromosomes 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.
Myriad Genetics, Inc.	RCV003449220	SCV004188301	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.
Baylor Genetics	RCV003464024	SCV004198110	likely pathogenic	Endometrial carcinoma	2022-11-25	criteria provided, single submitter	clinical testing