Submissions for variant NM_000179.3(MSH6):c.3312dup (p.Gly1105fs)

dbSNP: rs267608092

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130275	SCV000185120	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	clinical testing	The c.3312dupT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a duplication of T at nucleotide position 3312, causing a translational frameshift with a predicted alternate stop codon (p.G1105Wfs*3). This mutation was detected in 1/537 French families tested for Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10). This mutation has been identified as germline in patients with glioblastoma and occurred de novo in at least one of these individuals (Forsström LM et al. J Neuropathol Exp Neurol, 2017 Oct;76:848-853; Wagener R et al. Eur J Hum Genet, 2021 08;29:1301-1311). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545922	SCV000624844	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1105Trpfs*3) 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 Lynch syndrome and gliobastomas (PMID: 21642682, 28922847). This variant is also known as c.3305_3306insT (p.1102-fs-insT). ClinVar contains an entry for this variant (Variation ID: 141667). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130275	SCV000690344	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This variant causes a duplication of one nucleotide in exon 6 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with Lynch syndrome (PMID: 21642682) and in individuals affected with glioblastoma (PMID: 28922847, 33840814). 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.
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	RCV000130275	SCV001482284	pathogenic	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	research
GeneDx	RCV000503173	SCV004170708	pathogenic	not provided	2023-04-26	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 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; Also known as c.3305_3306insT (p.1102-fs-insT); This variant is associated with the following publications: (PMID: 18269114, 24362816, 24728327, 34873480, 21642682, 34729042, 28922847, 28888541, 33840814)
Myriad Genetics, Inc.	RCV003453074	SCV004188201	pathogenic	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003460919	SCV004198117	pathogenic	Endometrial carcinoma	2022-11-01	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000503173	SCV005199214	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing
ITMI	RCV000121582	SCV000085778	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000503173	SCV000592635	pathogenic	not provided		no assertion criteria provided	clinical testing