2-47806582-A-AAGTT

Position:

• chr2-47806582-A-AAGTT

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.3934_3937dupGTTA​(p.Ile1313fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,462 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.262

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 (HGNC:):

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 2-47806582-A-AAGTT is Pathogenic according to our data. Variant chr2-47806582-A-AAGTT is described in ClinVar as [Pathogenic]. Clinvar id is 418610.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.3934_3937dupGTTA	p.Ile1313fs	frameshift_variant	9/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3934_3937dupGTTA	p.Ile1313fs	frameshift_variant	9/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461462 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	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 at least two individuals with a clinical history of a Lynch syndrome-associated cancer and/or colon polyps, as well as individuals also diagnosed with breast cancer (Susswein et al., 2015; Yurgelun et al., 2015; Palmer et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 31447099, 30787465, 12019211, 17531815, 21120944, 25980754, 30612635, 32427313, 28369758, 18625694) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 15, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2022	The c.3934_3937dupGTTA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of GTTA at nucleotide position 3934, which is predicted to cause a translational frameshift with an alternate stop codon (p.I1313Sfs*7). In addition, in silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This alteration occurs at the 3' terminus of the MSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 93 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in patients with Lynch syndrome-associated cancers (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20; Susswein LR et al. Genet Med, 2016 08;18:823-32). This mutation has also been observed in the homozygous state in a child with clinical features consistent with constitutional mismatch repair deficiency (CMMRD) (Polubothu S et al. Br. J. Dermatol. 2017 11;177(5):e185-e186). This alteration was also detected in 1/5054 African American women with breast cancer (Palmer JR et al. J Natl Cancer Inst, 2020 12;112:1213-1221). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2022	This variant inserts 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the ATPase and C-terminal MSH2-binding domains (PMID: 12019211, 21120944). This variant has been reported in individuals affected with Lynch/suspected Lynch syndrome (PMID: 18625694, 25980754) , breast, colorectal, endometrial cancer (PMID:26681312), or in a homozygous individual affected with constitutional mismatch repair (PMID: 28369758). 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. -

Endometrial carcinoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 30, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Ile1313SerfsX7 variant was identified in 2 of 23380 proband chromosomes (frequency: 0.00009) from individuals or families undergoing hereditary cancer panel testing or with a history of Lynch syndrome associated cancer and/or polyps (Yurgelun_2015_25980754 , Susswein_2015_26681312). In a case report, a 23-month-old female presenting with abnormal cutaneous pigmentation since birth and a past history of mediastinal non-Hodgkin lymphoma diagnosed at 9 months was found to carry the variant in biallelism, being the offspring of a consanguineous marriage (the grandfathers were brothers) (Polubothu_2017_ 28369758 ). The variant was also identified in ClinVar (classified pathogenic by GeneDx, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), UMD-LSDB (5x as causal), and was not identified in dbSNP, GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors 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.3934_3937dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1313 and leads to a premature stop codon 7 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.rnIn summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 28, 2023

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

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 17, 2018

The p.Ile1313SerfsX7 variant in MSH6 has been reported in the heterozygous state in 2 individuals with clinical features of Lynch syndrome and in the homozygous state in one individual with constitutional mismatch repair deficiency syndrome (CMMRD; Yurgelun 2015, Susswein 2015, Polubothu 2017). This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 418610) and was absent from large population databases. In vitro functional studies provide some evidence that the p.Ile1313SerfsX7 variant may impact protein function by disrupting the MSH2 interaction domain of MSH6 (Guerrette 1998). However, these types of assays may not accurately represent biological function. This variant i s predicted to cause a frameshift, which alters the protein?s amino acid sequenc e beginning at position 1313 and leads to a premature termination codon 7 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NM D) and result in a truncated protein. Another variant at this position (c.3932_3 935dupAAGT), resulting in the same amino acid change, was classified as pathogen ic on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108166.2) . In summary, this variant meets criteria to be classified as pathogenic for Lyn ch Syndrome in an autosomal dominant manner based upon its presence in affected individuals, absence from the general population, functional evidence, having th e same amino acid change as an established pathogenic variant and the predicted impact on the protein. ACMG/AMP Criteria applied: PS1, PVS1_Strong, PM2, PS3_Su pporting, PS4_Supporting. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change creates a premature translational stop signal (p.Ile1313Serfs*7) in the MSH6 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome, family history of Lynch syndrome-associated cancers, and/or personal history of Lynch syndrome-associated cancers (PMID: 25980754, 26681312, 28369758). ClinVar contains an entry for this variant (Variation ID: 418610). Studies have shown that this premature translational stop signal results in skipping of exon 9 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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: rs760190301; hg19: chr2-48033721;