Submissions for variant NM_000179.3(MSH6):c.3699_3702del (p.Lys1233fs)

dbSNP: rs193922343

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030271	SCV000108129	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001263515	SCV000052938	pathogenic	Hereditary nonpolyposis colon cancer	2020-10-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3699_3702delAGAA (p.Lys1233AsnfsX6) 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 allele was found at a frequency of 4e-06 in 251238 control chromosomes. c.3699_3702delAGAA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Goldberg_2014, Bonadona_2011, Batte_2014, Raymond_2015). 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. 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000128914	SCV000172781	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	The c.3699_3702delAGAA (p.K1233Nfs*6) alteration, located in exon 8 (coding exon 8) of the MSH6 gene, consists of a deletion of 4 nucleotides from position 3699 to 3702, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/251238) total alleles studied. The highest observed frequency was 0.001% (1/113596) of European (non-Finnish) alleles. This mutation has been reported in multiple families with Lynch syndrome (Bonadona, 2011). Based on the available evidence, this alteration is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202074	SCV000257273	pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
GeneDx	RCV000202074	SCV000279110	pathogenic	not provided	2023-08-16	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 (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: 25980754, 25213678, 27443514, 21642682, 25430799, 28152038, 18389388, 30787465, 29922827, 32719484, 28888541, 35366121)
Invitae	RCV000524183	SCV000551259	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1233Asnfs*6) 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 present in population databases (rs267608115, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 18389388, 21642682). This variant is also known as c.3697_3700delAAAG. ClinVar contains an entry for this variant (Variation ID: 36593). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202074	SCV000601584	pathogenic	not provided	2021-03-26	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported in individuals with Lynch syndrome in the published literature (PMIDs: 25430799 (2015), 25980754 (2015), and 21642682 (2011)). Based on the available information, this variant is classified as pathogenic.
Counsyl	RCV000576542	SCV000677728	pathogenic	Lynch syndrome 5	2015-06-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128914	SCV000903767	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 8 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-associated cancers (PMID: 18389388, 21642682, 24933100, 27443514). This variant has been identified in 1/251238 chromosomes 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000576542	SCV002515807	pathogenic	Lynch syndrome 5	2021-09-24	criteria provided, single submitter	research	ACMG codes: PVS1, PS4M, PM2, PP5
Myriad Genetics, Inc.	RCV000576542	SCV004019085	pathogenic	Lynch syndrome 5	2023-03-30	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	RCV003466878	SCV004195845	pathogenic	Endometrial carcinoma	2022-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541030	SCV004759006	pathogenic	MSH6-related disorder	2024-02-14	criteria provided, single submitter	clinical testing	The MSH6 c.3699_3702delAGAA variant is predicted to result in a frameshift and premature protein termination (p.Lys1233Asnfs*6). This variant was reported in individuals with Lynch syndrome (examples, eTable 1. Bonadona V et al 2011. PubMed ID: 21642682; Goldberg Y et al 2014. PubMed ID: 25430799). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/36593/). Frameshift variants in MSH6 are considered pathogenic. This variant is interpreted as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000030271	SCV004835113	pathogenic	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	The c.3699_3702del variant in the MSH6 gene is located on the exon 8 and is predicted to shift the reading frame such that it introduces a premature translation termination codon (p.Lys1233Asnfs*6), resulting in an absent or disrupted protein product. This variant has been reported in multiple unrelated individuals with Lynch syndrome-related cancer (PMID: 25430799, 18389388, 28514183, 24933100, 25980754). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 36593) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (1/251238 chromosomes). Therefore, the c.3699_3702del (p.Lys1233Asnfs*6) variant in the MSH6 gene has been classified as pathogenic.