2-47801050-G-T

Variant names:

• chr2-47801050-G-T
• rs267608059
• NM_000179.3:c.3067G>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000179.3(MSH6):​c.3067G>T​(p.Glu1023*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.97

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47801050-G-T is Pathogenic according to our data. Variant chr2-47801050-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 89336.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47801050-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3067G>T	p.Glu1023*	stop_gained	Exon 4 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3067G>T	p.Glu1023*	stop_gained	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu1023X variant in MSH6 has been reported in 2 individuals with Lynch syndrome associated cancers, including colorectal cancer and endometrial cancer and segregated with disease in 1 affected relative. Tumors sampled from 1 individual lacked MSH6 expression by immunohistochemistry (IHC), whereas the tumor from the affected relative showed normal MSH6 by IHC (Nilbert 2009 PMID: 18566915, Klarskov 2011 PMID: 21836479, Shirts 2016 PMID: 26845104). This variant was absent from large population studies (gnomAD v.3.1.2). This nonsense variant leads to a premature termination codon at position 1023, 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 autosomal dominant Lynch syndrome. Additionally, this variant was classified as Pathogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89336). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting, PS3_Supporting. -

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 -

Lynch syndrome 5 Pathogenic:1

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. -

not provided Pathogenic:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89336). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and endometrial and breast cancer (PMID: 18566915, 21836479, 22495361, 26845104). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1023*) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1023* pathogenic mutation (also known as c.3067G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 3067. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. This mutation has been reported in multiple families with Lynch syndrome associated cancers (Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; Klarskov L et al. Am J Surg Pathol, 2011 Sep;35:1391-9; Okkels H et al. Appl. Immunohistochem. Mol. Morphol., 2012 Oct;20:470-7; Shirts BH et al. Genet Med, 2016 10;18:974-81). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.93
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs267608059; hg19: chr2-48028189;