Submissions for variant NM_000179.3(MSH6):c.3155_3156del (p.Glu1052fs)

dbSNP: rs63750833

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074805	SCV000108016	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000202199	SCV000149311	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	Frameshift 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 (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Hampel et al., 2005; Baglietto et al., 2010; Susswein et al., 2016); This variant is associated with the following publications: (PMID: 24434690, 28514183, 20028993, 26681312, 15872200, 30787465)
Ambry Genetics	RCV000115402	SCV000214795	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-30	criteria provided, single submitter	clinical testing	The c.3155_3156delAG pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3155 to 3156, causing a translational frameshift with a predicted alternate stop codon (p.E1052Vfs*13). This mutation was reported in an individual with rectal cancer diagnosed at age 87 whose family met Bethesda criteria (Hampel H et al. N. Engl. J. Med. 2005 May;352:1851-60), in a patient with endometrial cancer diagnosed at age 34 who met Bethesda criteria and whose tumor showed loss of expression of the MSH6 protein (Dondi G et al. Int J Mol Sci, 2020 Sep;21:), and in a patient with localized prostate cancer diagnosed at age 82 (Haraldsdottir S et al. Genet. Med. 2014 Jul;16:553-7). This alteration was also reported in 2/10030 individuals undergoing hereditary cancer panel testing through a clinical laboratory, and both individuals had endometrial cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). 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	RCV000524154	SCV000260422	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1052Valfs*13) 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 clinical features of Lynch syndrome (PMID: 15872200, 20028993, 26681312, 28514183). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 89340). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001263505	SCV000695840	pathogenic	Hereditary nonpolyposis colon cancer	2020-10-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3155_3156delAG (p.Glu1052ValfsX13) 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 247410 control chromosomes. c.3155_3156delAG has been reported in the literature in individuals affected with various types of cancer (Hampel_2005, Haraldsdottir_2014, susswein_2016, Espenschied_2017, Lu_2019). These data indicate that the variant is likely to be associated with disease. 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202199	SCV000889483	pathogenic	not provided	2016-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115402	SCV001340970	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-17	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 and families affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 15872200, 20028993, 26681312, 28514183, 29345684, 33003368), as well as in individuals affected with breast or ovarian cancer (PMID: 30128536) and prostate cancer (PMID: 24434690). 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.
Revvity Omics, Revvity	RCV000202199	SCV002017576	pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450958	SCV004188263	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	RCV003460676	SCV004195714	pathogenic	Endometrial carcinoma	2023-11-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074805	SCV004837168	pathogenic	Lynch syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The c.3155_3156del (p.Glu1052Valfs*13) variant in the MSH6 gene is located on the exon 4 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Glu1052Valfs*13), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with Lynch syndrome-associated cancers (PMID: 33003368, 29345684, 28514183, 24434690, 15872200). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 30376427, 18269114). The variant is reported in ClinVar as pathogenic (ID: 89340) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.3155_3156del (p.Glu1052Valfs*13) variant of MSH6 has been classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202199	SCV000257234	pathogenic	not provided		no assertion criteria provided	research