Submissions for variant NM_000179.3(MSH6):c.3253del (p.Thr1085fs)

dbSNP: rs1060502891

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460971	SCV000551088	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1085Profs*5) 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: 410419). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001019451	SCV001180811	pathogenic	Hereditary cancer-predisposing syndrome	2018-12-03	criteria provided, single submitter	clinical testing	The c.3253delA pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3253, causing a translational frameshift with a predicted alternate stop codon (p.T1085Pfs*5). 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269969	SCV001450365	pathogenic	not provided	2017-06-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469155	SCV002765957	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-11-25	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3253delA (p.Thr1085ProfsX5) 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 249750 control chromosomes. To our knowledge, no occurrence of c.3253delA 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003449145	SCV004187366	pathogenic	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.