Submissions for variant NM_000179.3(MSH6):c.1030C>T (p.Gln344Ter)

dbSNP: rs730881815

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570360	SCV000662558	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	The p.Q344* pathogenic mutation (also known as c.1030C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1030. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation was detected in a patient diagnosed with colorectal cancer at age 43; the tumor was MSI-H and IHC results were consistent with isolated loss of MSH6 expression (Giráldez MD et al. Clin. Cancer Res., 2010 Nov;16:5402-13). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865721	SCV002135578	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln344*) 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 (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20924129, 26446363, 30543514). ClinVar contains an entry for this variant (Variation ID: 479954). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451217	SCV004185868	pathogenic	Lynch syndrome 5	2023-08-11	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354541	SCV001549185	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Gln344X variant was identified in 9 of 508 proband chromosomes (frequency: 0.02) from Spanish and Portuguese individuals or families with nonpolyposis CRC/early onset CRC or HNPCC (Giráldez_2010_20924129, Pinto_2015_26446363). The variant was identified in 8 unrelated Portuguese families, co-occurring with a nonsense mutation (MSH2 c.2785C>T, p.(Arg929Ter), likely in the cis-configuration, with all families showing haplotypes (conserved alleles) consistent with a common ancestor (Pinto_2015_26446363). The variant was also identified in UMD-LSDB (1x as causal), and was not identified in dbSNP, ClinVar, Clinvitae, COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1030C>T variant leads to a premature stop codon at position 344 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.