Submissions for variant NM_000179.3(MSH6):c.2906_2907del (p.Tyr969fs)

dbSNP: rs786203924

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167441	SCV000218297	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-04	criteria provided, single submitter	clinical testing	The c.2906_2907delAT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2906 to 2907, causing a translational frameshift with a predicted alternate stop codon (p.Y969Lfs*5). This pathogenic mutation was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
Color Diagnostics, LLC DBA Color Health	RCV000167441	SCV000685331	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 25980754, 33693762). 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.
Invitae	RCV000707705	SCV000836814	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr969Leufs*5) 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 clinical features of Lynch syndrome (PMID: 25980754, 28514183). ClinVar contains an entry for this variant (Variation ID: 187691). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001589044	SCV001816779	pathogenic	not provided	2022-02-08	criteria provided, single submitter	clinical testing	Frameshift 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 in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers (Yurgelun 2015); This variant is associated with the following publications: (PMID: 28514183, 25980754, 32719484)
Myriad Genetics, Inc.	RCV003454422	SCV004185621	pathogenic	Lynch syndrome 5	2023-08-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001589044	SCV004221200	pathogenic	not provided	2023-05-07	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome and Lynch-related cancers (PMIDs: 28888541 (2017), 28514183 (2017), 25980754 (2015)). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV003995592	SCV004838956	pathogenic	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 25980754, 33693762). 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.