rs63750955

Positions:

• chr2-47798633-A-AT

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.651dupT​(p.Lys218fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,658 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift, stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 0.266

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]

MSH6 (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 2-47798633-A-AT is Pathogenic according to our data. Variant chr2-47798633-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 8932.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.651dupT	p.Lys218fs	frameshift_variant, stop_gained	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.651dupT	p.Lys218fs	frameshift_variant, stop_gained	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459446 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726056

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 AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

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: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 09, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2020	Nonsense 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 a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as MSH6 217insT, MSH6 650insT, and MSH6 651_652insT; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Wu 1999, Plaschke 2000, Wu 2001, Berends 2002, Berends 2003, Hendriks 2004, Domingo 2005, Kets 2006, Overbeek 2007, Ramsoekh 2008, Steinke 2008, Ou 2009, van der Post 2010); This variant is associated with the following publications: (PMID: 16636019, 15782118, 15483016, 10521294, 20591884, 11586295, 18301448, 14645426, 18521850, 17117178, 18625694, 15236168, 10699937, 11709755, 20028993, 17453009, 12373605, 21081928, 19156873, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2024	The MSH6 c.651dup (p.Lys218*) 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/families suspect of or diagnosed with Lynch Syndrome (PMID: 10521294 (1999), 17453009 (2007), 18625694 (2008), and 20028993 (2010)). It has also been described in an individual with a gynecological cancer (PMID: 34519692 (2022)), an individual with cancer in the urothelial tissue, colon, ureter, and prostate (PMID: 20591884 (2010)). In a large scale breast cancer association study, this variant has been observed in a breast cancer case (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 27, 2024	PM2, PS4_moderate, PVS1 -

Lynch syndrome 5 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 10, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2001	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 27, 2020	This variant inserts 1 nucleotide in exon 4 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 multiple families affected with Lynch syndrome and is considered to be a founder mutation in the Dutch population (PMID: 11709755, 25345868). This variant has been identified in 1/31412 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	Ambry Genetics	Jun 16, 2022	The c.651dupT pathogenic mutation (also known as p.K218*), located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 651. This changes the amino acid from a lysine to a stop codon within coding exon 4. In one study, this mutation was identified in three individuals with suspected HNPCC (Wu Y et al. Am J Hum Genet. 1999 Nov;65(5):1291-8). This mutation was also reported in an individual diagnosed with colon cancer at the age of 61, prostate cancer at the age of 67, and both ureter and bladder cancers at the age of 73. Immunohistochemistry (IHC) studies of the bladder tumor were reported to have absent MSH2 staining (van der Post RS et al. J Med Genet. 2010 Jul;47(7):464-70). Furthermore, this mutation has been identified in multiple other individuals with a clinical suspicion of Lynch syndrome and/or tumors exhibiting MSI-H and loss of MSH6 on IHC (Kets CM et al. Br. J. Cancer. 2006 Dec;95:1678-82; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16(5):587-92; Ramsoekh D et al. Gut 2008 Nov;57(11):1539-44). 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:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 06, 2022

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 18, 2022

Variant summary: MSH6 c.651dupT (p.Lys218X) 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 1.3e-05 in 150984 control chromosomes (gnomAD v3.1 database, genomes dataset). c.651dupT has been reported in the literature in multiple individuals affected with colorectal cancer and other tumors that belong to the Lynch Syndrome tumor spectrum (e.g. Plaschke_2000, Hendricks_2004, Kets_2006, Carnevali_2021); in some of these cases the lack of MSH6 protein on immunohistochemistry and/or high microsatellite instability was also noted in the associated tumor samples. 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. Seven other ClinVar submitters, have assessed the variant since 2014, and all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

MSH6-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2024

The MSH6 c.651dupT variant is predicted to result in premature protein termination (p.Lys218*). This variant has been reported in multiple individuals with Lynch syndrome (Wu et al. 1999. PubMed ID: 10521294; Hendriks et al. 2004. PubMed ID: 15236168; Steinke et al. 2008. PubMed ID: 18301448; Van der Post et al. 2010. PubMed ID: 20591884). This variant was also reported in a patient with autosomal recessive constitutional mismatch repair deficiency (CMMRD) syndrome who was heterozygous for both p.Lys218* and another MSH6 frameshift (c.3957dupA / p.Ala1320Serfs*4; Kroeze et al. 2022. PubMed ID: 34964038). The p.Lys218* variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/8932/). Nonsense variants in MSH6 are expected to be pathogenic. Taken together, the p.Lys218* variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change creates a premature translational stop signal (p.Lys218*) 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 (rs63750955, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and Lynch syndrome (PMID: 2059188, 10521294, 17453009, 18625694, 20028993). This variant is also known as 217insT. ClinVar contains an entry for this variant (Variation ID: 8932). For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

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- -

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: rs63750955; hg19: chr2-48025772;