chr2-47804984-T-TA

Position:

• chr2-47804984-T-TA

Variant summary

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

The NM_000179.3(MSH6):​c.3514dup​(p.Arg1172LysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,004 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: 0.0000096 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 1.73

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 2-47804984-T-TA is Pathogenic according to our data. Variant chr2-47804984-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 89404.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3514dup	p.Arg1172LysfsTer5	frameshift_variant	6/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3514dup	p.Arg1172LysfsTer5	frameshift_variant	6/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251324 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MSH6: PVS1, PP4:Moderate, PS4:Moderate, PM2:Supporting -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 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; Not observed at significant frequency in large population cohorts (gnomAD); 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: 16616355, 24728189, 32980694, 31830689, 29922827, 24689082, 18301448, 18566915, 21081928, 30521064, 34178123, 31589614, 33087929, 35273153, 37663290, 36425062, 33309985, 36437915, 36243179, 20587412, 27723366, 20682701, 10508506, 17453009, 28466842, 19072991, 15483016, 20591884) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 03, 2020	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 patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Lynch syndrome Pathogenic:4

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This variant inserts 1 nucleotide in exon 6 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 individuals affected with Lynch syndrome-associated cancer (PMID: 10508506, 18566915, 19130300, 20587412, 20591884, 20682701, 24728189, 28466842). This variant has been identified in 3/282730 chromosomes 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 19, 2018	Variant summary: MSH6 c.3514dupA (p.Arg1172LysfsX5) 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. The variant allele was found at a frequency of 1.1e-05 in 277060 control chromosomes (gnomAD). c.3514dupA has been reported in the literature in multiple individuals affected with Lynch Syndrome or related tumor phenotypes (Nilbert 2009, Schofield 2009, Sjursen 2010, Steinke2008, Wijnen 1999, Plaschke 2004, Haraldsdottir 2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2021	The p.Arg1172LysfsX5 variant in MSH6 has been previously reported in at least 14 individuals with Lynch syndrome or associated cancers, and segregated with disease in 3 affected relatives from 1 family (Wijnen 1999 PMID: 10508506, Plaschke 2004 PMID: 15483016, Jenkins 2006 PMID: 16616355, Overbeek 2007 PMID: 17453009, Steinke 2008 PMID: 18301448, Nilbert 2009 PMID: 19130300, van der Post 2010 PMID: 20591884, Sjursen 2010 PMID: 20587412, Woods 2010 PMID: 20682701, Song 2014 PMID: 24728189, Haraldsdottir 2017 PMID: 28466842, Jiang 2019 PMID: 30521064) and in 1 individual with constitutive mismatch repair deficiency in the compound heterozygous state (Soplepmann 2016 PMID: 27723366). It has been identified in 0.003% (1/35414) of Latino and in 0.002% (2/129076) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1172 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. Additionally, this variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108084.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PM3, PP1. -

Lynch syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 16, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 23, 2024	The c.3514dupA pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a duplication of A at nucleotide position 3514, causing a translational frameshift with a predicted alternate stop codon (p.R1172Kfs*5). This mutation has been identified in multiple families with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Overbeek LI et al. Br. J. Cancer. 2007 May;96:1605-12; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16:587-92; Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83; van der Post RS et al. J. Med. Genet. 2010 Jul;47:464-70; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; Haraldsdottir S et al. Nat. Commun. 2017 May;8:14755). This alteration has also been detected in conjunction with another MSH6 mutation in 17-year-old patient with a clinical diagnosis of congenital mismatch repair deficiency syndrome (Soplepmann J et al. Acta Oncol. 2016 Dec;55:1503-1505). 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	Feb 22, 2023	This variant inserts 1 nucleotide in exon 6 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 individuals affected with Lynch syndrome-associated cancer (PMID: 10508506, 18566915, 19130300, 20587412, 20591884, 20682701, 24728189, 28466842). This variant has been identified in 3/282730 chromosomes 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Arg1172LysfsX5 duplication variant was identified in 5 of 5380 proband chromosomes (frequency: 0.001) from individuals with colorectal cancer or other cancers associated with Lynch syndrome (Nilbert 2009, Overbeek 2007, Plaschke 2004, Schofield 2009, Wijnen 1999). This variant was also identified in dbSNP (ID: rs63751327), HGMD, UMD (7X), “Mismatch Repair Genes Variant Database”, and the “InSiGHT Colon Cancer Database”. The p.Arg1172LysfsX5 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1172 and leads to a premature stop codon at position 1176. This alteration is then predicted to result in a truncated or absent protein and loss of function. Two studies demonstrated a loss of MSH6 expression in tumours with the variant (Schofield 2009, You 2010), and loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change creates a premature translational stop signal (p.Arg1172Lysfs*5) 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 present in population databases (rs63751327, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and urothelial, colorectal, bladder and ovarian cancer (PMID: 10508506, 18566915, 19130300, 20587412, 20591884, 20682701, 24728189). This variant is also known as 1172insA or c.3514_3515insA. ClinVar contains an entry for this variant (Variation ID: 89404). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 28, 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: rs63751327; hg19: chr2-48032123;