Submissions for variant NM_000179.3(MSH6):c.3238_3239del (p.Leu1080fs)

dbSNP: rs863225406

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000554689	SCV000624833	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1080Valfs*12) 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 endometrial cancer (PMID: 24933100). ClinVar contains an entry for this variant (Variation ID: 218060). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000582996	SCV000690334	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 5 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 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.
Ambry Genetics	RCV000582996	SCV002611345	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-28	criteria provided, single submitter	clinical testing	The c.3238_3239delCT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3238 to 3239, causing a translational frameshift with a predicted alternate stop codon (p.L1080Vfs*12). This mutation was observed in a patient with MSH6-absent, MSI-H endometrial cancer diagnosed at age 65 who also had a family history of endometrial and colorectal cancer (Batte BA et al. Gynecol. Oncol. 2014 Aug;134:319-25). 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.
Myriad Genetics, Inc.	RCV003454529	SCV004185768	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000500492	SCV004848298	likely pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Leu1080ValfsX12 variant in MSH6 has been reported in 1 individual with endometrial cancer (Batte 2014) and was absent from large population studies. This variant has been reported in ClinVar (Variation ID 218060), classified as pathogenic by several clinical labs. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1080 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, the p.Leu1080ValfsX12 variant meets criteria to be classified as likely pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2.
Mayo Clinic Laboratories, Mayo Clinic	RCV000201961	SCV000257244	likely pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500492	SCV000592628	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The p.Leu1080ValfsX12 variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), Clinvitae, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, the ClinVar and UMD databases. The p.Leu1080ValfsX12 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1080 and leads to a premature stop codon 12 codons downstream. 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 this 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.
Laboratory for Genotyping Development, RIKEN	RCV003165480	SCV002758363	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research