NM_000179.3:c.2147_2148delCA

Variant names:

• chr2-47800126-GAC-G
• rs786204048
• NM_000179.3:c.2147_2148delCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000179.3(MSH6):​c.2147_2148delCA​(p.Thr716SerfsTer39) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T716T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.71
• Publications: 6 publications found

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]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 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 2-47800126-GAC-G is Pathogenic according to our data. Variant chr2-47800126-GAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 428317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.2147_2148delCA	p.Thr716SerfsTer39	frameshift_variant	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.2147_2148delCA	p.Thr716SerfsTer39	frameshift_variant	Exon 4 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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history including colorectal, pancreatic, and other cancers (Perez-Carbonell et al., 2012; Meric-Bernstam et al., 2016; Cloyd et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also reported as 2144_2145delAC; This variant is associated with the following publications: (PMID: 35449176, 29946497, 21868491, 29238914, 26787237) -

Mar 31, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.2147_2148del (p.Thr716Serfs*39) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. This variant has been reported in the published literature in individuals with colorectal cancer (PMID: 21868491 (2012)), biliary tract cancer and gastric cancer (PMID: 29238914 (2018)), and in a pancreatic tumor specimen (PMID: 26787237 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic -

Lynch syndrome 5 Pathogenic:1

Aug 16, 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. -

Lynch syndrome Pathogenic:1

Sep 10, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes two nucleotides from exon 4 of the MSH6 mRNA (c.2144_2145delAC), causing a frameshift at codon 716. This creates a premature translational stop signal 38 codons downstream (p.Thr716Serfs*39) and is expected to result in an absent or disrupted protein product. This sequence change has been reported in the literature and is not present in population databases. This sequence change was reported in an individual affected with colorectal cancer, who also was screened for and tested negative for mutations in other Lynch syndrome related genes. Screening of the tumor sample from this individual revealed microsatellite instability, but no loss of expression of any of the mismatch repair proteins (PMID: 21868491). This sequence change is also known as c.2147_2148delCA in the literature. In summary, this sequence change is absent from the general population and is expected to create an absent or aberrant MSH6 protein. For these reasons, this sequence change has been classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 27, 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.Thr716Serfs*39) 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: 21868491). ClinVar contains an entry for this variant (Variation ID: 428317). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2147_2148delCA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2147 to 2148, causing a translational frameshift with a predicted alternate stop codon (p.T716Sfs*39). This mutation has been reported in a family that met Amsterdam criteria where the proband was diagnosed with ascending colon cancer at the age of 79; while the tumor showed microsatellite instability, IHC staining showed MLH1, MSH2, MSH6, and PMS2 proteins were intact (Pérez-Carbonell L et al. Gut 2012 Jun;61:865-72). This variant was also reported in a female diagnosed with ampullary cancer, gastric cancer, and CML by age 40 (Cloyd JM et al. J Gastrointest Cancer, 2018 Mar;49:93-96). 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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Thr716SerfsX39 variant was identified in 1 of 4186 proband chromosomes (frequency: 0.0002) from Spanish individuals or families with CRC, the affected case meeting Amsterdam criteria (Perez-Cabornell_2011_21868491). The variant was also identified in dbSNP (ID: rs786204048) “With Pathogenic allele”, ClinVar (classified pathogenic by Invitae and Ambry Genetics), Clinvitae (2x), UMD-LSDB (2x as causal), Insight Colon Cancer Gene Variant Database (1x), Insight Hereditary Tumors Database (1x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2147_2148delCA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 716 and leads to a premature stop codon 39 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204048; hg19: chr2-48027265;