Submissions for variant NM_000179.3(MSH6):c.1805C>G (p.Ser602Ter)

dbSNP: rs730881816

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160715	SCV000211348	pathogenic	not provided	2021-05-19	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 in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in a patient with multiple cancers including renal cancer (Susswein 2016); This variant is associated with the following publications: (PMID: 31447099, 26681312)
Invitae	RCV000627696	SCV000283729	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser602*) 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 cancers associated with Lynch syndrome and renal cancer and a neuroectodermal tumor (PMID: 26681312; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182659). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000409404	SCV000488387	pathogenic	Lynch syndrome 5	2016-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491316	SCV000580257	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The p.S602* pathogenic mutation (also known as c.1805C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1805. This changes the amino acid from a serine to a stop codon within coding exon 4. This alteration was reported in 1/10030 individuals undergoing hereditary cancer panel testing through a clinical laboratory (Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000231648	SCV000712558	pathogenic	Lynch syndrome	2016-11-09	criteria provided, single submitter	clinical testing	The p.Ser602X variant in MSH6 has not been previously reported in individuals wi th Lynch Syndrome and was absent from large population studies. This nonsense va riant leads to a premature termination codon at position 602 which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the M SH6 gene is an established disease mechanism in Lynch Syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner based upon the predicted impact to the protein.
Color Diagnostics, LLC DBA Color Health	RCV000491316	SCV000905452	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000231648	SCV001338279	pathogenic	Lynch syndrome	2020-02-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1805C>G (p.Ser602X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250434 control chromosomes. c.1805C>G has been reported in the literature as a pathogenic variant in at-least one individual referred for genetic testing due to a reported clinical history of renal, sarcoma, and primitive neuroectodermal tumor (Susswein_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160715	SCV001469817	pathogenic	not provided	2020-07-21	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Revvity Omics, Revvity	RCV000160715	SCV003822249	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409404	SCV004018873	pathogenic	Lynch syndrome 5	2023-03-28	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.