Submissions for variant NM_000179.3(MSH6):c.2535dup (p.Glu846Ter)

dbSNP: rs587779241

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074751	SCV000107961	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Counsyl	RCV000410929	SCV000488331	pathogenic	Lynch syndrome 5	2016-03-08	criteria provided, single submitter	clinical testing
Invitae	RCV000530811	SCV000624767	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89286). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20487569). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu846*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074751	SCV000695817	likely pathogenic	Lynch syndrome	2017-06-26	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.2535dupT (p.Glu846X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (e.g. c.2731C>T, p.Arg911X; c.3013C>T, p.Arg1005X; c.3052_3053delCT, p.Leu1018fsX4). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120004 control chromosomes. The variant was reported in a family that fulfilled the Amsterdam II criteria, however two mutation-positive family members did not have cancer, one of which was above the age of onset. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, based on truncating nature of the variant, and the limited clinical data, this variant is classified as likely pathogenic.
Ambry Genetics	RCV001015798	SCV001176673	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	clinical testing	The c.2535dupT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 2535, causing a translational frameshift with a predicted alternate stop codon (p.E846*). This mutation has been previously reported in a cohort of Australian Lynch syndrome families (Talseth-Palmer BA et al. Hered Cancer Clin Pract. 2010 May;8:5). 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.
Myriad Genetics, Inc.	RCV000410929	SCV004019036	pathogenic	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV001015798	SCV004357654	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This variant inserts 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 been reported in an individual affected with Lynch syndrome in an Australian cohort of Lynch syndrome families (PMID: 20487569). 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.
All of Us Research Program, National Institutes of Health	RCV000074751	SCV004832753	pathogenic	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This variant inserts 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 been reported in an individual affected with Lynch syndrome in an Australian cohort of Lynch syndrome families (PMID: 20487569). 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.