rs587779259

Variant names:

• chr2-47803510-TCTTAGAG-T
• rs587779259
• NM_000179.3:c.3268_3274delGAGCTTA

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.3268_3274delGAGCTTA​(p.Glu1090LysfsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 7.99

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 2-47803510-TCTTAGAG-T is Pathogenic according to our data. Variant chr2-47803510-TCTTAGAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 89366.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47803510-TCTTAGAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3268_3274delGAGCTTA	p.Glu1090LysfsTer23	frameshift_variant	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.3268_3274delGAGCTTA	p.Glu1090LysfsTer23	frameshift_variant	Exon 5 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Feb 22, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of 7 nucleotides in MSH6 is denoted c.3268_3274delGAGCTTA at the cDNA level and p.Glu1090LysfsX23 (E1090KfsX23) at the protein level. The normal sequence, with the bases that are deleted in braces, is CTTA[GAGCTTA]AAGG. The deletion causes a frameshift, which changes a Glutamic Acid to a Lysine at codon 1090, and creates a premature stop codon at position 23 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3268_3274delGAGCTTA, also reported as c.3264_3270del, has been observed in at least one individual with Lynch syndrome (Canard 2012). we consider this variant to be pathogenic. -

Mar 22, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 frameshift predicted to result in premature protein truncation. -

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.Glu1090LysfsX23 variant was identified in 1 of 156 proband chromosomes (frequency: 0.006) from individuals or families with colorectal cancer (Talseth-Palmer 2010). The variant was also identified in dbSNP (ID: rs587779259) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic by InSight) and UMD (12x with a “causal” classification). The variant was not found in the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the genome Aggregation Database (beta), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database. However, this information is not predictive enough to assume pathogenicity. The c.3268_3274del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1090 and leads to a premature stop codon 23 codons downstream. This alteration is then predicted to result in 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. -

Lynch syndrome Pathogenic:1

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 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jun 23, 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.Glu1090Lysfs*23) 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 Lynch syndrome (PMID: 20487569, 21879275, 27601186). This variant is also known as c.3264_3270del. ClinVar contains an entry for this variant (Variation ID: 89366). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 06, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3268_3274delGAGCTTA pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of 7 nucleotides at nucleotide positions 3268 to 3274, causing a translational frameshift with a predicted alternate stop codon (p.E1090Kfs*23). This mutation has been previously reported in a an Australian cohort of individuals/families suspected of having HNPCC/Lynch syndrome based on clinical and/or family history (Talseth-Palmer BA et al. Hered Cancer Clin Pract. 2010 May;8:5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779259; hg19: chr2-48030649;