2-47803449-C-T

Variant names:

• chr2-47803449-C-T
• rs63749843
• NM_000179.3:c.3202C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_001406831.1(MSH6):​c.-18C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MSH6 NM_001406831.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:34
• Conservation: PhyloP100: 3.28

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.528
• PP5: Variant 2-47803449-C-T is Pathogenic according to our data. Variant chr2-47803449-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 89352.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47803449-C-T is described in Lovd as [Pathogenic]. Variant chr2-47803449-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3202C>T	p.Arg1068*	stop_gained	Exon 5 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3202C>T	p.Arg1068*	stop_gained	Exon 5 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:34

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:10

Apr 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 17, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_MOD, PVS1 -

Mar 27, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with personal and/or family history consistent with pathogenic variants in this gene (PMID: 11807791, 18301448, 20028993, 20379851, 20487569, 23403630, 26552419, 28528517, 30702970, 34178123); 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; 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: 23733757, 24323032, 20487569, 11807791, 18301448, 25741868, 25525159, 21247423, 20028993, 28152038, 26552419, 23403630, 15483016, 28002797, 20379851, 28528517, 29360161, 29489754, 30702970, 30324682, 30322717, 34178123, 34426522, 30787465, 33804961, 34887416, 36243179, 35798629, Tsukanov2023[CaseReport], 31447099, 37453313, 34326862, 35089076, 36988593, 31742824) -

Jan 21, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.00002 (3/152096 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with Lynch syndrome- associated cancers (PMIDs: 11807791 (2002), 18301448 (2008), 24323032 (2014), 28528517(2017), 29360161 (2018), 30324682 (2018), 30702970 (2019), 33422027 (2021), and 34178123 (2021)). Based on the available information, this variant is classified as pathogenic. -

May 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6: PVS1, PM2, PS4:Moderate -

Lynch syndrome 5 Pathogenic:8

Aug 22, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PM2_SUP,PP4 -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.3202C>T variant in the MSH6 gene has been reported in multiple rectal cancer, HNPCC and Lynch syndrome patients [PMID:18301448, 20028993, 24323032] while not observed in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidence, this c.3202C>T (p.Arg1068*) in the MSH6 gene is classified as pathogenic. -

Jul 03, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 5 of 10 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been reported in multiple individuals and families with Lynch syndrome-associated cancers such as colorectal cancer, endometrial cancer, pancreatic cancer and renal cancer (PMID: 11807791, 24323032, 20379851, 18301448, 20028993). This variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.3202C>T (p.Arg1068Ter) variant is classified as Pathogenic. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 08, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:4

Aug 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1068* pathogenic mutation (also known as c.3202C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3202. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families, several with tumors showing high microsatellite instability and/or absent MSH6 protein expression on IHC (Plaschke J et al. Int. J. Cancer, 2002 Feb;97:643-8; Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92; Baglietto L et al. J Natl Cancer Inst, 2010 Feb;102:193-201; Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; McIlvried DE et al. Fam. Cancer, 2010 Sep;9:377-81; Thodi G et al. BMC Cancer, 2010 Oct;10:544; Ward RL et al. J Clin Oncol, 2013 Jul;31:2554-62; Buchanan DD et al. J Clin Oncol, 2014 Jan;32:90-100; Goodfellow PJ et al. J Clin Oncol, 2015 Dec;33:4301-8; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Iordache PD et al. J Cell Mol Med, 2018 12;22:6068-6076; Dudley B et al. Cancer, 2018 04;124:1691-1700; Salvador MU et al. J Clin Oncol, 2019 03;37:647-657; Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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. -

Jan 09, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2_Supporting, PP4_Strong c.3202C>T, located in exon 5 of the MSH6 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). This variant was reported to cosegregate in two endometrial cancer-affected sisters (PMID: 20487569). There are several reports on this variant being associated to Lynch syndorme, and there are at least 4 independent CRC/Endometrial cancer patients reported to show isolated loss of MSH6 by IHC (PMID: 30324682, 20487569, 26552419) (PP4_Strong). To our knowledge, no well-established functional studies have been reported for this variant. This variant has been reported in the ClinVar database (31x pathogenic), in LOVD (multiple entries as (likely) pathogenic), and it has been classified as pathogenic by InSiGHT. Based on currently available information, the variant c.3202C>T should be considered a pathogenic variant according to MMR specific InSIGHT Guidelines, Draft v3.1. -

Dec 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 5 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 affected with Lynch syndrome or Lynch syndrome associated cancers (PMID: 11807791, 18301448, 20028993, 20379851, 20487569, 20937110, 24323032, 29967336). This variant has not been identified 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. -

Oct 28, 2015

Vantari Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation resulting in a stop codon -

Sep 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3202C>T (p.Arg1068*) variant in the MSH6 gene is located on the exon 5 and introduces a premature translation termination codon (p.Arg1068*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 30324682, 29360161, 33422027, 28528517, 20487569). Loss-of-function variants of MSH6 are known to be pathogenic, and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89352) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.3202C>T (p.Arg1068*) variant of MSH6 has been classified as pathogenic. -

Endometrial carcinoma Pathogenic:2

Jan 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Oct 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.3202C>T (p.Arg1068X) 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 was absent in 251326 control chromosomes. c.3202C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Baglietto_2010, Dudley_2018, Plaschke_2002, Steinke_2008, Talseth-Palmer_2010, Thodi_2010). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20028993, 29360161, 11807791, 18301448, 20487569, 20937110, 24362816, 25525159). 19 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Oct 30, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch-like syndrome Pathogenic:1

Jul 01, 2019

Constitutional Genetics Lab, Leon Berard Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1068*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer, endometrial cancer, pancreatic cancer, and renal cancer (PMID: 11807791, 18301448, 20028993, 20379851, 24323032). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 89352). For these reasons, this variant has been classified as Pathogenic. -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Arg1068X variant was identified in 8 of 3948 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome and endometrial cancer, and is classified as pathogenic in the literature (Buchanan 2014, Plaschke 2002, Plaschke 2004, Steinke 2008, Talseth Palmer 2010, Ward 2013, Castillejo 2011, Mcllvried 2010). The variant was also identified in the following databases: dbSNP (ID: rs63749843) as “With Pathogenic allele”, ClinVar (10x as pathogenic, reviewed by an expert panel), Clinvitae (4x as pathogenic), COGR, Cosmic (4x in colon cancer), UMD-LSDB (12x as "causal"), Insight Colon Cancer Gene Variant Database (15 x as pathogenic), and Mismatch Repair Genes Variant Database. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was also identified by our laboratory in 2 individuals with uterine and endometrial cancer. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg1068X variant leads to a premature stop codon at position 1068, 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 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. -

MSH6-related disorder Pathogenic:1

Oct 31, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3_Moderate, PM2 -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.95
GERP RS		2.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63749843; hg19: chr2-48030588; COSMIC: COSV52273620; COSMIC: COSV52273620;