Submissions for variant NM_000179.3(MSH6):c.3491dup (p.Cys1165fs)

dbSNP: rs876661073

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001731532	SCV000279457	pathogenic	not provided	2021-09-16	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 (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000491050	SCV000580159	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-06	criteria provided, single submitter	clinical testing	The c.3491dupT pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a duplication of T at nucleotide position 3491, causing a translational frameshift with a predicted alternate stop codon (p.C1165Vfs*7). 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	RCV000630084	SCV000751040	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1165Valfs*7) 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 variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 234542). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491050	SCV001343616	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 6 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 MSH6-related disorders in the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328390	SCV001519513	likely pathogenic	Hereditary nonpolyposis colon cancer	2021-03-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3491dupT (p.Cys1165ValfsX7) 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. The variant was absent in 251382 control chromosomes. To our knowledge, no occurrence of c.3491dupT in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 likely pathogenic.
Myriad Genetics, Inc.	RCV003454670	SCV004188197	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.
Baylor Genetics	RCV003469108	SCV004197733	likely pathogenic	Endometrial carcinoma	2023-09-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001731532	SCV004221229	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	The MSH6 c.3491dup (p.Cys1165Valfs*7) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has not been reported in individuals with MSH6-related conditions in the published literature. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MSH6 mRNA splicing. Based on the available information, this variant is classified as pathogenic.