Submissions for variant NM_000179.3(MSH6):c.1767del (p.Pro591fs)

dbSNP: rs1114167765

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491835	SCV000580298	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-17	criteria provided, single submitter	clinical testing	The c.1767delT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 1767, causing a translational frameshift with a predicted alternate stop codon (p.P591Qfs*19). This variant has been reported in one Australian Lynch syndrome individual (Sjursen W et al. Mol Genet Genomic Med. 2016 Mar;4:223-31). 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	RCV000554919	SCV000624683	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro591Glnfs*19) 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: 428393). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491835	SCV000912168	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-30	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 observed in an individual affected with Lynch syndrome (PMID: 27064304). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284176	SCV001469816	pathogenic	not provided	2019-10-04	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001284176	SCV001905560	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289660	SCV002579277	likely pathogenic	Lynch syndrome 5	2021-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307521	SCV002600629	pathogenic	Hereditary nonpolyposis colon cancer	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1767delT (p.Pro591GlnfsX19) 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 250300 control chromosomes. c.1767delT has been reported in the literature in individuals affected with Lynch Syndrome and Uterine corpus endometrial carcinoma (Sjursen_2016, Lu_2015). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV002289660	SCV004185666	pathogenic	Lynch syndrome 5	2023-08-15	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	RCV001355622	SCV004198108	pathogenic	Endometrial carcinoma	2022-12-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001284176	SCV005421349	pathogenic	not provided	2024-06-05	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 at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27064304)
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249965	SCV001423979	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355622	SCV001550557	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Pro591Glnfs*19 variant was identified in 1 of 1668 proband chromosomes (frequency: 0.001) from individuals or families with Lynch syndrome (Sjursen 2016). The variant was also identified in dbSNP (ID: rs1114167765) as "With Pathogenic allele" and ClinVar (classified as pathogenic by Invitae and Ambry Genetics). The variant was not identified in the 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.1767del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 591 and leads to a premature stop codon at position 609. 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. Further, this variant was identified by our laboratory in a patient with an MSH6-deficient endometrial tumour. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.