rs63750194

chr2-47804982-GAT-G

Variant summary

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

The NM_000179.3(MSH6):c.3513_3514del(p.Asp1171GlufsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. D1171D) 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 reviewed by expert panel P:12
• Conservation: PhyloP100: 8.92

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 2-47804982-GAT-G is Pathogenic according to our data. Variant chr2-47804982-GAT-G is described in ClinVar as [Pathogenic]. Clinvar id is 89403.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47804982-GAT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3513_3514del	p.Asp1171GlufsTer5	frameshift_variant	6/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3513_3514del	p.Asp1171GlufsTer5	frameshift_variant	6/10	1	NM_000179.3	P4

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

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	This deletion of two nucleotides in MSH6 is denoted c.3513_3514delTA at the cDNA level and p.Asp1171GlufsX5 (D1171EfsX5) at the protein level. The normal sequence, with the bases that are deleted in braces, is TTGA[TA]GAGT. The deletion causes a frameshift, which changes an Aspartic Acid to a Glutamic Acid at codon 1171, and creates a premature stop codon at position 5 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.3513_3514delTA has been reported in individuals with colorectal and endometrial cancer, with most tumors demonstrating abnormal mismatch repair protein expression, and is classified as pathogenic by the International Society for Gastrointestinal Hereditary Tumors Incorporated (Steinke 2008, Buchanan 2014, Thompson 2014, Kraus 2015). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2020	This variant deletes 2 nucleotides 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 29107668, 18301448, 14974087) and in individuals with endometrial or colorectal cancers (PMID: 25142776, 24323032). 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	curation	Sema4, Sema4	Feb 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2022	The c.3513_3514delTA pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a deletion of two nucleotides between positions 3513 and 3514, causing a translational frameshift with a predicted alternate stop codon (p.D1171Efs*5). This alteration was previously reported in a man with ascending colon cancer at 31 years whose tumor demonstrated high microsatellite instability and isolated absence of MSH6 on immunohistochemistry (IHC) (Plaschke J et al. Hum Mutat. 2004 Mar;23(3):285). This alteration was also reported in a woman diagnosed with serous endometrial cancer at 51 years whose tumor demonstrated isolated absence of MSH6 on IHC (Buchanan DD et al. J. Clin. Oncol. 2014 Jan;32(2):90-100). This alteration has been reported in a man diagnosed with colon cancer at age 56 years whose tumor demonstrated microsatellite stability and normal protein expression on IHC (Kraus C et al. Int. J. Cancer. 2015 Mar 15;136(6):E559-68). Additionally, this alteration has been detected in a Polish patient with prostate cancer (Wokoorczyk D et al. Int J Cancer. 2020 11;147:2793-2800). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Lynch syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 24, 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	MGZ Medical Genetics Center	Nov 08, 2021	- -

Lynch syndrome Pathogenic:2

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2017	The p.Asp1171fs variant in MSH6 has been reported in 3 individuals with Lynch sy ndrome associated cancers (Plaschke 2004, Buchanan 2014 Steinke 2008). This vari ant was absent from large population studies, though the ability of these studie s to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at posit ion 1171 and leads to a premature termination codon 5 amino acids downstream. Th is alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as p athogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar S CV000108082.2). In summary, this variant meets criteria to be classified as path ogenic for Lynch syndrome in an autosomal dominant manner based upon the predict ed impact to the protein and absence from controls. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2023

This sequence change creates a premature translational stop signal (p.Asp1171Glufs*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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 89403). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750194; hg19: chr2-48032121;