rs587782111

Positions:

• chr2-47804946-T-TA

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.3476dup​(p.Tyr1159Ter) variant causes a stop gained, frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 stop_gained, frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.75

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 2-47804946-T-TA is Pathogenic according to our data. Variant chr2-47804946-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3476dup	p.Tyr1159Ter	stop_gained, frameshift_variant	6/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3476dup	p.Tyr1159Ter	stop_gained, frameshift_variant	6/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2022	PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2024	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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 27329137, 28514183, 30376427); 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: 30376427, 24755471, 28514183, 28152038, 28696559, 28502729, 27329137, 31447099, 22081473, 24362816, 18269114, 21868491, 21642682, 34687117, 32719484, 35346574, 33804961, 35070997, 36974724, 36974006, 35660797) -

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 23, 2023

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

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 12, 2023

Variant summary: MSH6 c.3476dupA (p.Tyr1159X) 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 was absent in 254684 control chromosomes. c.3476dupA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and Lynch Syndrome (Chubb_2016, Espenschied_2017, Rey_2017, Latham_2019). These data indicate that the variant is likely to be associated with disease. In addition, the c.3477C>A and c.3477delC variants that cause the same nonsense change, p.Tyr1159X, have been reported in multiple affected individuals (Bonadona_2011, Marignol_2008, Perez-Cabonell_2011, Van Lier_2012).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

MSH6-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2023

The MSH6 c.3476dupA variant is predicted to result in premature protein termination (p.Tyr1159*). This variant was reported in the homozygous state in a pediatric lymphoma patient [reported as c.3476dupA (p.Tyr1159_Val1160delins*) in Sylvester et al. 2021. PubMed ID: 34687117]. This variant was also reported in a Lynch syndrome cohort (Espenschied et al. 2017. PubMed ID: 28514183), as well as in the heterozygous state in individuals with breast cancer (Supplemental Table S3, Tran et al. 2022. PubMed ID: 35070997), and colon cancer (referred to as c.3475_3476insA in Supplementary Table 3, Chubb et al. 2016. PubMed ID: 27329137; Rey et al. 2017. PubMed ID: 28502729). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/141918/). Nonsense variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 14, 2017

The p.Tyr1159X (c.3476_3477insA) variant in MSH6 has not been previously reporte d in the literature, but has been reported in ClinVar by other clinical laborato ries (Variation ID# 141918). This variant was absent from large population studi es. This nonsense variant leads to a premature termination codon at position 115 9, which is predicted to lead to a truncated or absent protein. Heterozygous los s of function of the MSH6 gene is an established disease mechanism in Lynch synd rome. Another nonsense variant at an adjacent nucleotide position (c.3477C>A) th at results in the same amino acid change has been reported in two individuals wi th Lynch syndrome (Perez-Carbonell 2010 and Bonadona 2011). Microsatellite inst ability was documented in the individual reported (Perez-Carbonell 2010). In sum mary, this variant meets criteria to be classified as pathogenic for Lynch syndr ome in an autosomal dominant manner based upon the predicted impact to the prote in and absence from controls. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 141918). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 27329137, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1159*) 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

The c.3476dupA pathogenic mutation (also known as p.Y1159*), located in coding exon 6 of the MSH6 gene, results from a duplication of A at nucleotide position 3476. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This alteration was identified in a patient diagnosed with early onset colon cancer (Latham A et al. J. Clin. Oncol., 2019 Feb;37:286-29). Two other alterations resulting in the same premature stop codon (c.3477C>A and c.3477delC) have been identified in multiple individuals suspected of having Lynch syndrome (Bonadona V et al. JAMA. 2011 Jun;305:2304-10; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74). 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. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 23, 2022

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Computational scores

Source: dbNSFP v4.3

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: rs587782111; hg19: chr2-48032085;