Submissions for variant NM_000179.3(MSH6):c.3108_3109del (p.Phe1037fs)

dbSNP: rs1553414519

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000630021	SCV000750977	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1037Leufs*2) 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 (PMID: 27064304). ClinVar contains an entry for this variant (Variation ID: 525755). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781601	SCV000919773	likely pathogenic	Lynch syndrome	2018-11-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3108_3109delGT (p.Phe1037LeufsX2) 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 (e.g., p.Glu1052fsX13 and p.Arg1068X). The variant was absent in 244248 control chromosomes (gnomAD). The variant, c.3108_3109delGT, has been reported in the literature in individuals affected with Lynch Syndrome (Sjursen_2015, DeRycke_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001018672	SCV001179937	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-26	criteria provided, single submitter	clinical testing	The c.3108_3109delGT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3108 to 3109, causing a translational frameshift with a predicted alternate stop codon (p.F1037Lfs*2). This mutation was previously identified in an Australian cohort of HNPCC/Lynch syndrome patients (Sjursen W et al. Mol Genet Genomic Med. 2016 Mar;4:223-31) and was also reported in 1 of 1231 colorectal cancer cases in another large study (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). 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.
Color Diagnostics, LLC DBA Color Health	RCV001018672	SCV001352405	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 4 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 been reported in individuals affected with Lynch syndrome and colorectal cancer (PMID: 27064304, 28944238). 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.
Genetics and Molecular Pathology, SA Pathology	RCV002466553	SCV002761380	pathogenic	Lynch syndrome 5	2019-10-01	criteria provided, single submitter	clinical testing	The c.3108_3109del variant has been reported multiple times in the scientific literature in association with Lynch syndrome (Sjursen et al. 2016 PMID: 27064304, DeRyke et al. 2017 PMID: 28944238, Slavin et al. 2018 PMID: 28687971).
CeGaT Center for Human Genetics Tuebingen	RCV000656573	SCV004183743	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2
Myriad Genetics, Inc.	RCV002466553	SCV004188258	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	RCV003459494	SCV004195675	pathogenic	Endometrial carcinoma	2023-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656573	SCV004221205	pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing	The MSH6 c.3108_3109del (p.Phe1037Leufs*2) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. In the published literature, this variant has been reported in individuals affected with Lynch syndrome (PMIDs: 28944238 (2017), 27064304 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000781601	SCV004848297	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Phe1037LeufsX2 variant in MSH6 has been reported in 2 individuals with colorectal cancer and 1 individual with pancreatic cancer (Sjursen 2016, DeRycke 217, Slavin 2018). It was absent from large population studies. This variant has been reported in ClinVar (Variation ID 525755), classified as pathogenic by 1 clinical lab. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1037 and leads to a premature termination codon 2 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.Phe1037LeufsX2 variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656573	SCV000778621	likely pathogenic	not provided	2018-02-12	no assertion criteria provided	clinical testing