Submissions for variant NM_000179.3(MSH6):c.1483C>T (p.Arg495Ter)

dbSNP: rs587779212

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074659	SCV000107861	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000131420	SCV000186400	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-11	criteria provided, single submitter	clinical testing	The p.R495* pathogenic mutation (also known as c.1483C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1483. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been identified in multiple individuals/families with HNPCC/Lynch syndrome based on personal and family history (Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; Dominguez-Valentin M et al. BMC Urol. 2016 Mar;16:15; Beggs AD et al. Breast J. Jan;19:193-5). This alteration has been identified in a cohort of Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835) and in a cohort of Latin American patients suspected of having Lynch syndrome (Rossi BM et al. BMC Cancer. 2017 Sep;17:623). This alteration was also detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing. (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074659	SCV000266090	pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000202276	SCV000279096	pathogenic	not provided	2021-03-31	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; Not observed at a significant frequency 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 individuals with a personal and/or family history of Lynch syndrome associated cancers (Brinkman 2006, Sjursen 2010, Bonadona 2011, Beggs 2013, Carneiro da Silva 2015, Shirts 2016, Lagerstedt-Robinson 2016, Tian 2019); This variant is associated with the following publications: (PMID: 20587412, 23294250, 26845104, 31054147, 21642682, 17100999, 27013479, 26437257, 27601186, 27742654, 28724667, 28874130)
Invitae	RCV000524112	SCV000551164	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg495*) 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 (rs587779212, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20587412, 21642682, 26437257, 27601186). ClinVar contains an entry for this variant (Variation ID: 89197). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202276	SCV000888241	pathogenic	not provided	2018-04-09	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000074659	SCV000914308	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000202276	SCV002017591	pathogenic	not provided	2019-06-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000202276	SCV004033730	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PS4:Moderate
Human Genetics Bochum, Ruhr University Bochum	RCV003334381	SCV004042780	pathogenic	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4, PM2_SUP
Myriad Genetics, Inc.	RCV003334381	SCV004188257	pathogenic	Lynch syndrome 5	2023-08-14	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	RCV003460662	SCV004195576	pathogenic	Endometrial carcinoma	2023-08-20	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131420	SCV004228018	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202276	SCV004243087	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131420	SCV004357592	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a 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 Lynch syndrome (PMID: 20587412, 21642682, 23294250, 26437257, 27601186, 27013479, 28874130) and breast cancer (PMID: 33471991, 28724667). This variant has been identified in 1/251182 chromosomes 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	RCV000074659	SCV004843688	pathogenic	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a 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 Lynch syndrome (PMID: 20587412, 21642682, 23294250, 26437257, 27601186, 27013479, 28874130) and breast cancer (PMID: 33471991, 28724667). This variant has been identified in 1/251182 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074659	SCV004848628	pathogenic	Lynch syndrome	2022-03-01	criteria provided, single submitter	clinical testing	The p.Arg495X variant in MSH6 has been reported in at least 7 individuals with MSH6-associated cancers and at least 1 individual with breast cancer (Sjursen 2010 PMID: 20587412, Bonadona 2011 PMID: 21642682, Beggs 2013 PMID: 23294250, Carneiro da Silva 2015 PMID: 26437257, Lagerstedt-Robinson 2016 PMID: 27601186, Rossi 2017 PMID: 28874130, Sun 2017 PMID: 28724667, Tian 2019 PMID: 31054147). It has also been identified in 0.003% (1/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 495, which is predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Additionally, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar Variation ID 89197). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202276	SCV000257212	likely pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353858	SCV000592586	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Arg495X variant has been reported in the HGMD, COSMIC, InSiGHT databases and once in the literature in 5 out of 1028 proband chromosomes in individuals with HNPCC. However, no controls were tested to establish the frequency of the variant in the general population (Sjursen 2010). The variant leads to a premature stop codon at position 495 which is predicted to cause premature truncation of the protein product. This is a loss of function DNA variant and loss of function the MSH6 gene is an established disease mechanism for Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic.
Gharavi Laboratory, Columbia University	RCV000202276	SCV000809460	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249984	SCV001423998	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000202276	SCV001906068	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202276	SCV001963242	pathogenic	not provided		no assertion criteria provided	clinical testing