rs730881830

Positions:

• chr2-47806588-T-TTC

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.3939_3940dup​(p.Gln1314LeufsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.23

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 2-47806588-T-TTC is Pathogenic according to our data. Variant chr2-47806588-T-TTC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3939_3940dup	p.Gln1314LeufsTer14	frameshift_variant	9/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3939_3940dup	p.Gln1314LeufsTer14	frameshift_variant	9/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461432 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727018

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 22, 2022	The c.3939_3940dupTC (p.Gln1314Leufs*14) variant in MSH6 gene creates a frameshift that results in a premature termination codon, predicted to cause truncated or absent of protein product due to nonsense mediated decay. This variant has been reported in an individual screened for mismatch repair mutations whose phenotype was not described (PMID: 28514183), in an individual with breast cancer (PMID: 29345684) and in an individual who was diagnosed with colorectal and bladder cancer (PMID: 26681312). Other frameshift variants affecting the same amino acid frame, c.3938_3941dupTTCA, c.3941_3942insTC has been reported to cause endometrial cancer, colorectal cancer and Lynch syndrome (PMID: 18269114, 26099011, 22658618, 30608896). Several truncating variants downstream of this variant region have been determined to be pathogenic and cause various cancer types (PMID:24440087, 19851887, 14520694). Truncating loss of function variants in MSH6 are known to be pathogenic (PMID: 14974087, 2815724, 18269114, 24362816). This variant was found to be absent in the general population according to gnomAD. Therefore, c.3939_3940dupTC (p.Gln1314Leufs*14) variant of MSH6 gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	The p.Gln1314fs variant in MSH6 has been reported in 1 individual with colorecta l and bladder cancer and 1 individual with unspecified cancer (Susswein 2015, Es penschied 2017). It has also been reported in ClinVar (Variation ID 182683) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a f rameshift, which alters the protein?s amino acid sequence beginning at position 1314 and leads to a premature termination codon 14 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 (NMD), resulting in a trun cated protein. Truncating variants downstream of this variant have been reported in individuals with Lynch syndrome. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Gln1314fs variant is likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 03, 2022	This variant inserts 2 nucleotides in exon 9 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 been reported in an individual affected with bladder and colorectal cancer (PMID: 26681312) and in an individual undergoing screening for mismatch repair gene mutations (PMID: 28514183). 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	clinical testing	Ambry Genetics	Apr 16, 2022	The c.3939_3940dupTC pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of TC at nucleotide position 3939, causing a translational frameshift with a predicted alternate stop codon (p.Q1314Lfs*14). This mutation has been identified in an individual who was diagnosed with bladder and colorectal cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 17, 2020

Variant summary: MSH6 c.3939_3940dupTC (p.Gln1314LeufsX14) 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 249986 control chromosomes. c.3939_3940dupTC has been reported in the literature in an individual affected with colorectal and bladder cancer (Susswein_2015) and in an individual screened for MMR mutations (phenotype not specified, Espenschied_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2024

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ovarian cancer and other individuals undergoing multi-gene panel testing whose cancer history was unclear (PMID: 26681312, 28514183, 28888541, 31447099); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26681312, 28152038, 28514183, 19851887, 14520694, 24440087, 28888541, 31447099) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change creates a premature translational stop signal (p.Gln1314Leufs*14) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal and bladder cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182683). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 19851887, 24440087). 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. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

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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: rs730881830; hg19: chr2-48033727;