Submissions for variant NM_000179.3(MSH6):c.1634_1635del (p.Lys545fs)

dbSNP: rs267608064

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129244	SCV000184003	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	clinical testing	The c.1634_1635delAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of 2 nucleotides at positions 1634 and 1635 causing a translational frameshift with a predicted alternate stop codon (p.K545Rfs*17). This alteration was previously reported in trans with another MSH6 pathogenic mutation in a child with constitutional mismatch repair deficiency (CMMR-D) syndrome (Peters A et al. J. Pediatr. Hematol. Oncol. 2009 Feb;31(2):113-5). 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.
GeneDx	RCV000202281	SCV000565783	pathogenic	not provided	2022-09-07	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 Lynch syndrome-associated cancer and/or colon polyps (Yurgelun et al., 2015; Ring et al., 2016); This variant is associated with the following publications: (PMID: 28888541, 26681312, 21674763, 28152038, 25980754, 27443514, 30787465, 33087929, 19194194)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202281	SCV000601511	pathogenic	not provided	2015-02-26	criteria provided, single submitter	clinical testing
Invitae	RCV000558194	SCV000624671	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys545Argfs*17) 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 colorectal cancer and lymphoblastic lymphoma (PMID: 19194194, 26681312). ClinVar contains an entry for this variant (Variation ID: 140961). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129244	SCV000905450	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-08	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 observed in individuals with suspected Lynch syndrome (PMID: 25980754 ), colorectal cancer (PMID: 26681312), and endometrial cancer (PMID: 27443514). 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.
Mendelics	RCV000986717	SCV001135809	likely pathogenic	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532548	SCV004114864	pathogenic	MSH6-related disorder	2023-03-23	criteria provided, single submitter	clinical testing	The MSH6 c.1634_1635delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys545Argfs*17). This variant has been reported in a cohort of individuals with suspected Lynch syndrome (Table S1 - Yurgelun et al. 2015. PubMed ID: 25980754). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140961/). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV000986717	SCV004188196	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	RCV003467107	SCV004196338	pathogenic	Endometrial carcinoma	2022-02-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997490	SCV004841768	pathogenic	Lynch syndrome	2023-05-30	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 observed in individuals affected with suspected Lynch syndrome (PMID: 25980754 ), colorectal cancer (PMID: 26681312), and endometrial cancer (PMID: 27443514). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003997490	SCV004848291	pathogenic	Lynch syndrome	2024-03-21	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Mayo Clinic Laboratories, Mayo Clinic	RCV000202281	SCV000257215	pathogenic	not provided		no assertion criteria provided	research