rs267608114

Positions:

• chr2-47806353-CAT-C

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.3799_3800delAT​(p.Met1267fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 8.85

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 2-47806353-CAT-C is Pathogenic according to our data. Variant chr2-47806353-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 89463.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806353-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3799_3800delAT	p.Met1267fs	frameshift_variant, splice_region_variant	8/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3799_3800delAT	p.Met1267fs	frameshift_variant, splice_region_variant	8/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461820 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2019	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -
Likely pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2017	This deletion of two nucleotides in MSH6 is denoted c.3799_3800delAT at the cDNA level and p.Met1267GlyfsX7 (M1267GfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAT[delAT]GGTA. The deletion causes a frameshift which changes a Methionine to a Glycine at codon 1267, and creates a premature stop codon at position 7 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.3799_3800delAT has been reported in individuals with Lynch syndrome (Nilbert 2009, Klarskov 2011). We consider this variant to be pathogenic. -

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 25, 2023

This variant is considered pathogenic. This variant creates a frameshift 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

Dec 21, 2023

Variant summary: MSH6 c.3799_3800delAT (p.Met1267GlyfsX7) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251216 control chromosomes (gnomAD). c.3799_3800delAT has been reported in the literature in at-least one individuals affected with Hereditary Nonpolyposis Colorectal Cancer (example: Nilbert_2009). The following publications have been ascertained in the context of this evaluation (PMID: , 18566915, 25255306). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change creates a premature translational stop signal (p.Met1267Glyfs*7) 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 clinical features of Lynch syndrome (PMID: 18566915, 21836479). ClinVar contains an entry for this variant (Variation ID: 89463). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.3799_3800delAT pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3799 to 3800, causing a translational frameshift with a predicted alternate stop codon (p.M1267Gfs*7). This mutation has been detected in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including an individual whose tumor demonstrated high microsatellite instability and loss of MSH6 by immunohistochemistry (IHC) (Nilbert M et al. Fam Cancer. 2009;8(1):75-83; Klarskov L et al. Am J Surg Pathol, 2011 Sep;35:1391-9). 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

May 19, 2023

- -

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: rs267608114; hg19: chr2-48033492;