Submissions for variant NM_000179.3(MSH6):c.1901T>A (p.Leu634Ter)

dbSNP: rs63751097

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759849	SCV000889466	pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Invitae	RCV001061933	SCV001226697	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu634*) 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 premature translational stop signal has been observed in individual(s) with endometrial cancer (PMID: 12732731, 15098177). ClinVar contains an entry for this variant (Variation ID: 619873). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001805840	SCV002052836	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-23	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). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV000759849	SCV002526467	pathogenic	not provided	2022-06-17	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 significant frequency in large population cohorts (gnomAD); 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	RCV001805840	SCV002722635	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	clinical testing	The p.L634* pathogenic mutation (also known as c.1901T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 1901. This changes the amino acid from a leucine 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.
Myriad Genetics, Inc.	RCV003453560	SCV004188272	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.
All of Us Research Program, National Institutes of Health	RCV003999908	SCV004835533	pathogenic	Lynch syndrome	2023-06-20	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). To date, this variant has not been reported in association with MSH6-related disease in the medical literature. A different variant (c.1901_1902del) that results in p.Leu634Ter has been reported in association with Lynch syndrome (PMID: 12732731; ClinVar ID 89232).