Submissions for variant NM_000179.3(MSH6):c.3332_3335dup (p.Asp1112delinsGluTer)

dbSNP: rs587782562

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV000202177	SCV000257251	pathogenic	not provided	2020-07-10	criteria provided, single submitter	clinical testing	PVS1, PM2, PP4
Ambry Genetics	RCV000131783	SCV000275618	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	clinical testing	The c.3332_3335dupATGA pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a duplication of ATGA at nucleotide position 3332, causing a translational frameshift with a predicted alternate stop codon (p.D1112Efs*2). This mutation has been identified in multiple families with Lynch syndrome (Rosty C et al. Fam. Cancer, 2014 Dec;13:573-82; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Baglietto L et al. J. Natl. Cancer Inst., 2010 Feb;102:193-201). Of note, this alteration is also designated as c.3335_3336insATGA and c.3336_3337insATGA in published literature. 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.
Invitae	RCV000524172	SCV000283798	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1112Glufs*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 present in population databases (rs587782562, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and Lynch syndrome and endometrial cancer (PMID: 19698169, 20028993, 25117503, 26552419). ClinVar contains an entry for this variant (Variation ID: 218061). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000233414	SCV000966977	pathogenic	Lynch syndrome	2018-07-13	criteria provided, single submitter	clinical testing	The p.Asp1112GlufsX2 variant in MSH6 has been reported in at least 3 families wi th Lynch Syndrome-related cancers and segregated with disease in at least one af fected relative (Choi 2009, Rosty 2014, Goodfellow 2015). This variant has also been reported in ClinVar (Variation ID# 218061). This variant has been identifie d in 1/111584 European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org). This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 1112 and leads to a premature termination codon 2 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch Syndro me. In summary, this variant meets criteria to be classified as pathogenic for L ynch Syndrome in an autosomal dominant manner based upon the presence in affecte d probands, low frequency in controls, and the predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193123	SCV001361759	pathogenic	Hereditary nonpolyposis colon cancer	2019-01-09	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3332_3335dupATGA (p.Asp1112GlufsX2) 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 (e.g. c.3476dupA (p.Tyr1159X), c.3477C>G (p.Tyr1159X), and c.3513_3514delTA (p.Asp1171fsX5)). The variant allele was found at a frequency of 4.1e-06 in 246100 control chromosomes (gnomAD). c.3332_3335dupATGA has been reported in the literature in individuals affected with Lynch Syndrome or related tumor phenotypes (Choi_2009, Goodfellow_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000202177	SCV001765754	pathogenic	not provided	2021-04-27	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 (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Choi 2009, Rosty 2014, Baglietto 2015, Goodfellow 2015, Graham 2015); This variant is associated with the following publications: (PMID: 31447099, 19698169, 25117503, 26552419, 26099011, 20028993)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202177	SCV002047257	pathogenic	not provided	2021-01-21	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of MSH6 protein synthesis. In the published literature, this variant has been reported in individuals/families affected with colorectal cancer and/or prostate cancer (PMIDs: 19698169 (2009), 20028993 (2010)) as well as endometrial cancer (PMID: 26552419 (2015)). Therefore, the variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003454530	SCV004187399	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202177	SCV000592636	pathogenic	not provided		no assertion criteria provided	clinical testing