2-47800056-CA-CAA

Position:

• chr2-47800056-CA-CAA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000179.3(MSH6):​c.2079dup​(p.Cys694MetfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000682 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.79

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47800056-C-CA is Pathogenic according to our data. Variant chr2-47800056-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 187516.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.2079dup	p.Cys694MetfsTer4	frameshift_variant	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.2079dup	p.Cys694MetfsTer4	frameshift_variant	4/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461858 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

Gnomad4 AFR AF: 0.0000242

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Cys694Metfs*4 variant was identified in 2 of 3472 proband chromosomes (frequency: 0.0006) from individuals or families with colorectal, cervical, or prostate cancer (Hansen 2017, Shirts 2015). The variant was also identified in dbSNP (ID: rs267608083) as “With Pathogenic allele”, ClinVar (classified as pathogenic by Ambry Genetics, Invitae, GeneDx and one other clinical laboratory), UMD-LSDB (1x causal), and Insight Hereditary Tumors Database (2x). The variant was not identified in the COGR, Cosmic, Zhejiang University Database, or Mismatch Repair Genes Variant database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.2079dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 694 and leads to a premature stop codon at position 697. 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	This duplication of one nucleotide in MSH6 is denoted c.2079dupA at the cDNA level and p.Cys694MetfsX4 (C694MfsX4) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CAAAAA[dupA]TGCC. The duplication causes a frameshift which changes a Cysteine to a Methionine at codon 694, and creates a premature stop codon at position 4 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.2079dupA has been reported in individuals with personal and/or a family history of colorectal cancer (Shirts 2016, Hansen2017). Based on currently available evidence, we consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 31, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 2021	The c.2079dupA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of A at nucleotide position 2079, causing a translational frameshift with a predicted alternate stop codon (p.C694Mfs*4). This mutation has been detected in multiple colorectal cancer patients (DeRycke MS et al. Mol Genet Genomic Med. 2017 Jul 23;5:553-569; Hansen MF et al. Clin Genet. 2017 Oct;92:405-414). Of note, this alteration is designated as c.2073_2074insA 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant inserts 1 nucleotide in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Apr 20, 2021	- -

Lynch syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2021	The p.Cys694MetfsX4 variant in MSH6 has been reported in 2 individuals with colorectal cancer (DeRycke 2017 PMID: 28944238, Hansen 2017 PMID: 28195393, Xavier 2019 PMID: 31297992) and in 1 individual with a family history of Lynch-associated tumors (Shirts 2016 PMID: 26845104). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 187516) and is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 694 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 16, 2023

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

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 187516). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 21520333, 28195393). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys694Metfs*4) 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). -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 11, 2022

- -

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: rs267608083; hg19: chr2-48027195;