Submissions for variant NM_000179.3(MSH6):c.1352del (p.Phe451fs)

dbSNP: rs869312769

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210100	SCV000266089	pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000684808	SCV000551304	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe451Serfs*2) 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 small intestine cancer and polyposis (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224534). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000480743	SCV000571367	pathogenic	not provided	2018-07-31	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH6 is denoted c.1352delT at the cDNA level and p.Phe451SerfsX2 (F451SfsX2) at the protein level. The normal sequence, with the base that is deleted in braces, is GTAT[T]CATG. The deletion causes a frameshift which changes a Phenylalanine to a Serine at codon 451, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Ambry Genetics	RCV000490853	SCV000580124	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	clinical testing	The c.1352delT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 1352, causing a translational frameshift with a predicted alternate stop codon (p.F451Sfs*2). This alteration was detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). This variant has also been identified in individuals with Lynch syndrome, including a patient with MSI-H cancer of the small intestine (Shirts BH et al. Genet Med, 2016 10;18:974-81; Patel AP et al. JAMA Netw Open, 2020 04;3:e203959). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000210100	SCV001338278	likely pathogenic	Lynch syndrome	2020-02-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1352delT (p.Phe451SerfsX2) 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 251008 control chromosomes (gnomAD). c.1352delT has been reported in the literature in at least one individual affected with small intestine cancer and polyposis (Shirts_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 (4x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000490853	SCV001346913	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 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.
Myriad Genetics, Inc.	RCV003454553	SCV004188283	pathogenic	Lynch syndrome 5	2023-08-14	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	RCV003468972	SCV004195843	pathogenic	Endometrial carcinoma	2023-01-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480743	SCV004221141	pathogenic	not provided	2022-05-14	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in an individual with cancer of the small intestine and in a healthy control individual (PMIDs: 26845104 (2016) and 33471991 (2021); https://databases.lovd.nl/shared/). Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000480743	SCV000691926	likely pathogenic	not provided		no assertion criteria provided	clinical testing