Submissions for variant NM_000179.3(MSH6):c.3103C>T (p.Arg1035Ter)

gnomAD frequency: 0.00001  dbSNP: rs63749999

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074803	SCV000108014	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000524153	SCV000260888	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1035*) 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 (rs63749999, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with clinical features of Lynch syndrome (PMID: 15236168, 15483016, 22006311, 23047549). ClinVar contains an entry for this variant (Variation ID: 89338). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000223452	SCV000273005	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	clinical testing	The p.R1035* pathogenic mutation (also known as c.3103C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 3103. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been detected in multiple individuals diagnosed with endometrial cancer whose family histories were suspicious for Lynch syndrome (Planck M et al. Int. J. Cancer 1999 Oct;83(2):197-202; Hendriks YM et al. Gastroenterology 2004 Jul;127(1):17-25; Devlin LA et al. Ulster Med. J. 2008 Jan;77(1):25-30). This mutation was also reported in an individual diagnosed with colon cancer with a tumor exhibiting high microsatellite instability and absent MSH6 expression on IHC (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108(44):18032-7). 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.
GeneDx	RCV000484829	SCV000568723	pathogenic	not provided	2020-08-24	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; This variant is associated with the following publications: (PMID: 12362848, 15236168, 10471527, 18269114, 25525159, 22658618, 23047549, 18301448, 15483016, 26720728, 24728189, 22006311, 25006859, 27863258, 27372833, 29489754, 30147880, 32660107, 30719162, 31307542, 32719484)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484829	SCV000601559	pathogenic	not provided	2022-11-25	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.000012 (3/247790 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021)), colorectal cancer (PMID: 27372833 (2016)), ovarian cancer (PMID: 26720728 (2016), 23047549 (2012), 22006311 (2011)), and endometrial cancer (PMID: 18301448 (2008), 18269114 (2004), 15236168 (2004), 10471527 (1999)). In addition, the variant has been detected in an individual with constitutional mismatch repair deficiency (CMMRD) syndrome who was compound heterozygous for the variant and a pathogenic MSH6 variant (PMID: 30147880 (2018)). Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002477211	SCV000894282	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-05-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223452	SCV000904986	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-27	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. This variant has been reported in individuals and families affected with Lynch syndrome-associated cancers (PMID: 10471527, 15236168, 15483016, 18269114, 18301448, 22006311, 25006859, 26720728, 27601186). This variant has been identified in 3/247790 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194362	SCV001363850	pathogenic	Hereditary nonpolyposis colon cancer	2019-09-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3103C>T (p.Arg1035X) 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. The variant allele was found at a frequency of 1.2e-05 in 247790 control chromosomes (gnomAD). c.3103C>T has been reported in the literature in multiple individuals with personal and family history of HNPCC-associated tumors (most commonly endometrial and/or ovarian cancer) and with loss of MSH6 protein expression and microsatellite instability identified in tumor samples (e.g. Devlin_2008, Hendriks_2004, Pal_2012, Planck_1999, Plasche_2004). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000484829	SCV001449828	pathogenic	not provided	2015-11-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000484829	SCV001713986	pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing	PP4, PP5, PS4_moderate, PVS1
Genetics and Molecular Pathology, SA Pathology	RCV000074803	SCV002556804	pathogenic	Lynch syndrome	2019-08-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000484829	SCV003827872	pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450957	SCV004187420	pathogenic	Lynch syndrome 5	2023-08-22	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	RCV001355855	SCV004195831	pathogenic	Endometrial carcinoma	2023-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074803	SCV004837135	pathogenic	Lynch syndrome	2024-01-09	criteria provided, single submitter	clinical testing	The c.3103C>T variant in the MSH6 gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg1035*), resulting in an absent or disrupted protein product. This variant has been reported in multiple unrelated individuals with Lynch syndrome-associated cancer (PMID: 34667028, 25006859, 31307542, 27601186, 18269114, 27372833, 15483016). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89338) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (3/247790 chromosomes). Therefore, the c.3103C>T (p.Arg1035*) variant in the MSH6 gene has been classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074803	SCV004848296	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Arg1035X variant in MSH6 has been previously reported in 1 individual with consitutive mismatch repair deficiency syndrome (compound heterozygous), 1 individual with pediatric CNS tumor, 1 individual with ovarian cancer and 6 individuals with endometrial cancer (1 of whom also carried a nonsense variant in BRIP1), and segregatted with disease in 2 affected relatives from 2 families (Pal 2102, Norquist 2016, Planck 1999, Hendriks 2004, Devlin 2008, Planschke 2004, Ling 2018, Grobner 2018). It has also been identified in 1/18338 of East Asian and 2/112342 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89338). This nonsense variant leads to a premature termination codon at position 1035, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate, PM3.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000074803	SCV005045717	pathogenic	Lynch syndrome	2021-08-05	criteria provided, single submitter	clinical testing	The c.3103C>T variant in the MSH6 gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg1035*), resulting in an absent or disrupted protein product. This variant has been reported in multiple unrelated individuals with Lynch syndrome-associated cancer (PMID: 34667028, 25006859, 31307542, 27601186, 18269114, 27372833, 15483016). Loss-of-function variants of MSH6 are known to be pathogenic (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89338) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (3/247790 chromosomes). Therefore, the c.3103C>T (p.Arg1035*) variant in the MSH6 gene has been classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355855	SCV001550860	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Arg1035X variant was identified in 4 of 816 proband chromosomes (frequency: 0.005) from individuals or families with Lynch Syndrome, and was not identified in 38 control chromosomes from healthy individuals (Everett 2014, Hendriks 2004, Pritchard 2012). The variant was identified in dbSNP (ID: rs63749999) as “With Pathogenic Allele”, in Clinvitae and Clinvar databases (pathogenic by InSIGHT, Invitae and Ambry Genetics), in COSMIC (1x with confirmed somatic status) and in InSiGHT Colon Cancer Gene Variant Database (2x as class 5 pathogenic). In addition, the variant was identified the Exome Aggregation Consortium database (August 8th 2016) in 1 of 119020 chromosomes (freq. 0.000008) in the European (Non-Finnish) population but not seen in the African, East Asian, Finnish, Latino, and South Asian populations and in the genome Aggregation Database (beta, October 19th 2016) in 2 of 242594 chromosomes (freq. 0.000008). The variant was not identified in Mismatch Repair Genes Variant, MMR Gene Unclassified Variants, Zhejiang Colon Cancer (LOVD), GeneInsight - COGR database, UMD, the 1000 Genomes and the NHLBI GO Exome Sequencing Projects databases. The p.Arg1035X variant leads to a premature stop codon at position 1035, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000484829	SCV001809720	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000484829	SCV001921072	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484829	SCV001951131	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000484829	SCV001970791	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162473	SCV002758546	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research