Submissions for variant NM_000179.3(MSH6):c.1168_1170delinsAA (p.Asp390fs)

dbSNP: rs863225398

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000202004	SCV000566481	pathogenic	not provided	2022-01-05	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; Identified in healthy individuals undergoing clinical exome sequencing in published literature (Grzymski 2020); This variant is associated with the following publications: (PMID: 32719484)
Ambry Genetics	RCV000491518	SCV000580160	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	clinical testing	The c.1168_1170delGATinsAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from the deletion of 3 nucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.D390Nfs*21). This alteration has been identified in several individuals with MSH6-deficient colon or endometrial cancers and/or whose family history meets Amsterdam I/II criteria (Ambry internal data; Lucas E et al. Int J Gynecol Pathol. 2019 Nov;38:533-542). This alteration was also identified in a Hispanic female diagnosed with endometrial adenocarcinoma with equivocal MSH2 and MSH6 expression on IHC and a metachronous peritoneal mesothelioma 10 months later (Lu Y et al. Int J Surg Pathol. 2017 May;25:253-257). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202004	SCV000601503	pathogenic	not provided	2021-05-08	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported among a cohort individuals with hereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia (PMID: 32719484 (2020)). Therefore, the variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804174	SCV000919726	pathogenic	Hereditary nonpolyposis colon cancer	2021-12-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1168_1170delinsAA (p.Asp390AsnfsX21) 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 251000 control chromosomes. To our knowledge, no occurrence of c.1168_1170delinsAA in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, the variant was reported once among 29,606 participants in the Healthy Nevada Project (HNP) that aimed to identity carriers of autosomal dominant diseases by population screening (example, Grzymski_2020). It is not specified whether this individual had clinically relevant disease. 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 (n=6). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491518	SCV001734833	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This variant deletes 3 nucleotides and inserts two new 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. 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.
Revvity Omics, Revvity	RCV000202004	SCV002017579	pathogenic	not provided	2019-05-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454524	SCV004187409	pathogenic	Lynch syndrome 5	2023-08-11	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	RCV003468929	SCV004195689	pathogenic	Endometrial carcinoma	2023-07-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997046	SCV004843048	pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant deletes 3 nucleotides and inserts two new 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. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202004	SCV000257207	likely pathogenic	not provided		no assertion criteria provided	research