Submissions for variant NM_000179.3(MSH6):c.3633dup (p.Val1212fs)

dbSNP: rs587776706

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507938	SCV000601580	pathogenic	not provided	2017-05-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774609	SCV000908425	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-01	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 7 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251416 chromosomes 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.
Ambry Genetics	RCV000774609	SCV001182289	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-31	criteria provided, single submitter	clinical testing	The c.3633dupT variant, located in coding exon 7 of the MSH6 gene, results from a duplication of T at nucleotide position 3633, causing a translational frameshift with a predicted alternate stop codon (p.V1212Cfs*3). This variant, referred to as c.3633insT, was reported, in the homozygous state, in a patient with constitutional mismatch repair deficiency syndrome, who was diagnosed with a glioblastoma at age 8 and T-cell lymphoma at age 10 (Bakry D et al. Eur. J. Cancer. 2014 Mar;50:987-96; Shlien A et al. Nat. Genet. 2015 Mar;47:257-62). 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.
Invitae	RCV001069945	SCV001235145	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-24	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 8941). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome (PMID: 16000562). This variant is present in population databases (rs762783821, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Val1212Cysfs*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).
Myriad Genetics, Inc.	RCV003450623	SCV004185707	pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
All of Us Research Program, National Institutes of Health	RCV003996081	SCV004835107	pathogenic	Lynch syndrome	2023-11-14	criteria provided, single submitter	clinical testing	The c.3633dup (p.Val1212Cysfs*3) variant in the MSH6 gene is located on the exon 7 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Val1212Cysfs*3), resulting in an absent or disrupted protein product. The variant has been reported in individuals with constitutional mismatch repair deficiency syndrome in recessive condition (PMID: 31501241, 24440087). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). Immunohistochemistry analysis and MMR activity assay from patient cells showed negative functional impact of this variant (PMID: 30608896). The variant is reported in ClinVar (ID: 8941). The variant is rare in the general population according to gnomAD (1/251416). Therefore, the c.3633dup (p.Val1212Cysfs*3) variant of MSH6 has been classified as pathogenic.
OMIM	RCV000009497	SCV000029715	pathogenic	Mismatch repair cancer syndrome 1	2005-07-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355519	SCV001550431	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Val1212Cysfs*3 variant was identified in the literature, although the frequency in an affected population was not provided (Hegde 2005, Durno 2010). The variant was identified in homozygous state in two children with Turcot Syndrome; both parents were found to be heterozygous for the same variant and did not have any cancer diagnoses (Hegde 2005). The variant was also identified in dbSNP (ID: rs587776706 as "With Pathogenic allele") and ClinVar (classified as pathogenic by two submitters) and was not identified in UMD-LSDB database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.3633dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1212 and leads to a premature stop codon at position 1214. This alteration is then predicted to result in 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.