Submissions for variant NM_000179.3(MSH6):c.3476dup (p.Tyr1159Ter)

dbSNP: rs587782111

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130627	SCV000185503	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	The c.3476dupA pathogenic mutation (also known as p.Y1159*), located in coding exon 6 of the MSH6 gene, results from a duplication of A at nucleotide position 3476. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This alteration was identified in a patient diagnosed with early onset colon cancer (Latham A et al. J. Clin. Oncol., 2019 Feb;37:286-29). Two other alterations resulting in the same premature stop codon (c.3477C>A and c.3477delC) have been identified in multiple individuals suspected of having Lynch syndrome (Bonadona V et al. JAMA. 2011 Jun;305:2304-10; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202052	SCV000257256	likely pathogenic	not provided	2022-03-16	criteria provided, single submitter	clinical testing	PM2, PVS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607246	SCV000731759	pathogenic	Lynch syndrome	2017-07-14	criteria provided, single submitter	clinical testing	The p.Tyr1159X (c.3476_3477insA) variant in MSH6 has not been previously reporte d in the literature, but has been reported in ClinVar by other clinical laborato ries (Variation ID# 141918). This variant was absent from large population studi es. This nonsense variant leads to a premature termination codon at position 115 9, which is predicted to lead to a truncated or absent protein. Heterozygous los s of function of the MSH6 gene is an established disease mechanism in Lynch synd rome. Another nonsense variant at an adjacent nucleotide position (c.3477C>A) th at results in the same amino acid change has been reported in two individuals wi th Lynch syndrome (Perez-Carbonell 2010 and Bonadona 2011). Microsatellite inst ability was documented in the individual reported (Perez-Carbonell 2010). In sum mary, this variant meets criteria to be classified as pathogenic for Lynch syndr ome in an autosomal dominant manner based upon the predicted impact to the prote in and absence from controls.
GeneDx	RCV000202052	SCV000779579	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Nonsense 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 patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Chubb et al., 2016; Espenschied et al., 2017; Latham et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30376427, 24755471, 28514183, 28152038, 28696559, 28502729, 27329137, 31447099, 22081473, 24362816, 18269114, 21868491, 21642682, 34687117, 32719484)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003103734	SCV000917756	pathogenic	Hereditary nonpolyposis colon cancer	2023-01-12	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3476dupA (p.Tyr1159X) 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 254684 control chromosomes. c.3476dupA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and Lynch Syndrome (Chubb_2016, Espenschied_2017, Rey_2017, Latham_2019). These data indicate that the variant is likely to be associated with disease. In addition, the c.3477C>A and c.3477delC variants that cause the same nonsense change, p.Tyr1159X, have been reported in multiple affected individuals (Bonadona_2011, Marignol_2008, Perez-Cabonell_2011, Van Lier_2012).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. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000819698	SCV000960374	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-08-01	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: 141918). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 27329137, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1159*) 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).
PreventionGenetics, part of Exact Sciences	RCV004528855	SCV004112367	pathogenic	MSH6-related disorder	2023-05-08	criteria provided, single submitter	clinical testing	The MSH6 c.3476dupA variant is predicted to result in premature protein termination (p.Tyr1159*). This variant was reported in the homozygous state in a pediatric lymphoma patient [reported as c.3476dupA (p.Tyr1159_Val1160delins*) in Sylvester et al. 2021. PubMed ID: 34687117]. This variant was also reported in a Lynch syndrome cohort (Espenschied et al. 2017. PubMed ID: 28514183), as well as in the heterozygous state in individuals with breast cancer (Supplemental Table S3, Tran et al. 2022. PubMed ID: 35070997), and colon cancer (referred to as c.3475_3476insA in Supplementary Table 3, Chubb et al. 2016. PubMed ID: 27329137; Rey et al. 2017. PubMed ID: 28502729). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/141918/). Nonsense variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV003453077	SCV004188306	pathogenic	Lynch syndrome 5	2023-08-23	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.
Baylor Genetics	RCV003461995	SCV004198157	pathogenic	Endometrial carcinoma	2022-04-23	criteria provided, single submitter	clinical testing