Submissions for variant NM_000179.3(MSH6):c.3013C>T (p.Arg1005Ter)

dbSNP: rs63750563

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074795	SCV000108006	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000202164	SCV000279556	pathogenic	not provided	2023-11-11	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 significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in the heterozygous state in individuals with Lynch syndrome (PMID: 15483016, 21247423, 27928858); Observed with a pathogenic MSH6 variant in an individual with constitutional mismatch repair-deficiency (CMMR-D) (PMID: 29130549); This variant is associated with the following publications: (PMID: 21247423, 23544471, 29130549, 29922827, 25525159, 15483016, 26203307, 26552419, 24278394, 27928858, 28944238, 33087929, 1958182, 32660107, 30572730, 32719484, 29625052)
Ambry Genetics	RCV000491215	SCV000580099	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	The p.R1005* pathogenic mutation (also known as c.3013C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 3013. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been identified in multiple individuals diagnosed with hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome (Plaschke, J et al. J Clin Oncol. 2004 Nov 15;22(22):4486-94; Castillejo, A et al. BMC Med Genet. 2011 Jan 19;12:12; Adachi M et al. Obstet. Gynaecol. Res. 2017 Feb;43(2):416-420; De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Keränen A et al. Scand J Gastroenterol, 2018 Dec;53:1535-1540; Olkinuora A et al. Cancers (Basel), 2020 Jul;12; Ambry internal data). This mutation has also been reported in an individual with constitutional mismatch repair deficiency (CMMRD) (Guerrini-Rousseau L et al. Neurooncol Adv Dec;1:vdz033). Of note, this alteration is also designated as p.R1005X 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202164	SCV000601553	pathogenic	not provided	2015-05-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001263506	SCV000695837	pathogenic	Hereditary nonpolyposis colon cancer	2020-10-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3013C>T (p.Arg1005X) 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 allele was found at a frequency of 4.8e-06 in 209220 control chromosomes (gnomAD). c.3013C>T has been reported in the literature in multiple individuals affected with colorectal cancer and Lynch syndrome (Plaschke_2004, Castillejo_2011, DeLellis_2013, Adachi_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000624966	SCV000743211	pathogenic	Lynch syndrome 5	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000624966	SCV000744294	pathogenic	Lynch syndrome 5	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491215	SCV000903435	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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 identified in 1/209220 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.
Invitae	RCV000808924	SCV000949057	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1005*) 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 (rs63750563, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with colorectal cancer, endometrial cancer and suspected of having Lynch syndrome (PMID: 15483016, 21247423, 23544471, 26552419, 27928858, 28944238). ClinVar contains an entry for this variant (Variation ID: 89330). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000202164	SCV001250449	pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202164	SCV001450228	pathogenic	not provided	2014-07-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202164	SCV002760665	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000202164	SCV003820211	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000624966	SCV004176408	pathogenic	Lynch syndrome 5	2023-03-01	criteria provided, single submitter	clinical testing	The stop gained variant c.3013C>T(p.Arg1005Ter) in MSH6 gene has been reported in heterozygous state in mutliple individuals with hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome (Adachi M, et al., 2017). The variant has 0.0005% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Thompson BA, et al., 2014). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000624966	SCV004187415	pathogenic	Lynch syndrome 5	2023-08-21	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	RCV003460674	SCV004196368	pathogenic	Endometrial carcinoma	2021-06-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074795	SCV004834455	pathogenic	Lynch syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with MSH6-related cancer and in at least one individual with constitutional mismatch repair deficiency and a second MSH6 loss-of-function variant (PMID: 29130549, 27928858, 21247423). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074795	SCV004848295	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Arg1005X variant in MSH6 has been previously reported in 5 individuals with colorectal cancer, 1 individual with endometrial cancer, 1 individual with multiple colorectal adenomas, and 2 individuals with Lynch syndrome, and segregated with disease in 2 affected relatives from 1 family (Colley 2005, Castillejo 2011, Plaschke 2004, De Lellis2013, Goodfellows 2015, Adachi 2017, Pan 2019, Keranen 2018, Tanskanen 2013). It has also been identified in 1/99286 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 89330). This nonsense variant leads to a premature termination codon at position 1005, 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202164	SCV000257231	pathogenic	not provided		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202164	SCV001955027	pathogenic	not provided		no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000624966	SCV004022209	likely pathogenic	Lynch syndrome 5	2023-07-21	no assertion criteria provided	research	The variant NM_000179.3:c.3013C>T (chr2:47800996) in MSH6 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.