Submissions for variant NM_000179.3(MSH6):c.3840_3846del (p.Glu1281fs)

dbSNP: rs63751319

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074942	SCV000108156	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000219135	SCV000279616	pathogenic	not provided	2023-03-31	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; Observed in individuals with MSH6-related cancers (Barnetson et al., 2006; Devlin et al., 2008; Baglietto et al., 2010; Pearlman et al., 2019); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as Q1280fsX1324; This variant is associated with the following publications: (PMID: 16807412, 20028993, 30877237, 18269114, 30787465)
Invitae	RCV000627732	SCV000283824	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1281Leufs*44) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (Lynch syndrome) (PMID: 16807412, 18269114, 20028993). ClinVar contains an entry for this variant (Variation ID: 89474). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Ala1320Glufs*6) have been determined to be pathogenic (PMID: 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000409718	SCV000488433	likely pathogenic	Lynch syndrome 5	2016-03-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491396	SCV000580217	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	The c.3840_3846delGGAGACT pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a deletion of 7 nucleotides at nucleotide positions 3840 to 3846, causing a translational frameshift with a predicted alternate stop codon (p.E1281Lfs*44). This mutation has been reported in a 44-year-old female with transverse colon cancer who met Bethesda guidelines for testing (Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63), as well as in an individual from a cohort of patients described as HNPCC-like due to clustering of HNPCC-related cancers or early age of diagnosis (Devlin LA et al. Ulster Med. J. 2008 Jan;77:25-30). This mutation was also observed in a patient with MSH6-absent colorectal cancer (Haraldsdottir S et al. Fam. Cancer. 2016 Apr;15:253-60). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074942	SCV000695892	pathogenic	Lynch syndrome	2017-06-20	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3840_3846delGGAGACT (p.Glu1281Leufs) 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.3938_3941dupTTCA, p.Gln1314fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120874 control chromosomes and has been reported in at least 2 affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491396	SCV000905460	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-22	criteria provided, single submitter	clinical testing	This variant deletes 7 nucleotides in exon 9 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 16807412), individuals affected with Lynch syndrome or colorectal cancer and clinical features of Lynch syndrome (PMID: 18269114, 26666765). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219135	SCV002047323	pathogenic	not provided	2021-02-23	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported in patients with Lynch Syndrome in the published literature (PMIDs: 16807412 (2006), 18269114 (2008), 20028993 (2010), 26666765 (2015), and 30877237 (2019)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000409718	SCV004018996	pathogenic	Lynch syndrome 5	2023-03-29	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	RCV003460693	SCV004197747	pathogenic	Endometrial carcinoma	2023-09-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356105	SCV001551176	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Glu1281Leufs*44 variant was identified in 3 of 2216 proband chromosomes (frequency: 0.001) from individuals or families with colorectal or endometrial cancer, or Lynch syndrome (Baglietto 2010, Barnetson 2006, Devlin 2008). The variant was also identified in dbSNP (ID: rs63751319 as "With Pathogenic allele"), ClinVar (5x as pathogenic by InSight, GeneDx, Invitae, Ambry Genetics, and Integrated Genetics/Laboratory Corporation of America and 1x as likely pathogenic by Counsyl), COGR, and Insight Hereditary Tumors databases. The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, the Mismatch Repair Genes Variant database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3840_3846del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1281 and leads to a premature stop codon at position 1324. This alteration is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in MSH6-associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.