rs267608078

chr2-47803500-AC-Achr2-47803500-AC-ACCchr2-47803500-AC-ACCC

Variant summary

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

The NM_000179.3(MSH6):c.3261del(p.Phe1088SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T1085T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:28 O:1
• Conservation: PhyloP100: 0.649

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 2-47803500-AC-A is Pathogenic according to our data. Variant chr2-47803500-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 89363.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47803500-AC-A is described in Lovd as [Pathogenic]. Variant chr2-47803500-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3261del	p.Phe1088SerfsTer2	frameshift_variant	5/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3261del	p.Phe1088SerfsTer2	frameshift_variant	5/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150382 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: 0.0000964

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1459644 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 726290

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000562

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150382 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73330

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: 0.0000964

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000340 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MSH6: PVS1, PS4:Moderate -
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	Revvity Omics, Revvity	Jan 04, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2021	This variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. In the published literature, this variant has been reported in individuals affected with a Lynch syndrome associated cancer (PMIDs: 20028993 (2010), 20591884 (2010), 22734033 (2012), 26787237 (2016), 29371908 (2018)) and CMMRD (PMID: 32042422 (2020)). The frequency of this variant in the general population, 0.000014 (4/280876 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2021	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 a significant frequency in large population cohorts (Lek 2016); Observed in the heterozygous state in patients with Lynch-related cancers consistent with pathogenic variants in this gene (Plaschke 2004, Hampel 2005, Baglietto 2010, Sjursen 2010, Talseth-Palmer 2010, Meric-Bernstam 2016); 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: 26552419, 26787237, 15872200, 29371908, 20591884, 20028993, 15483016, 20487569, 20587412, 26866578, 27601186, 27486176, 25980754, 10508506, 22734033, 26681312, 28528517, 26318770, 30730459, 30322717, 30093976, 31447099, 31845022, 31921681, 32832836, 32042422, 17557300, 32719484, 30787465, 33087929) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 18, 2017	The MSH6 c.3261delC, p.Phe1088fs variant (rs267608078) is a recurrent alteration in individuals diagnosed with hereditary nonpolyposis colorectal cancer and other familial cancers (Baglietto 2010, Lavoine 2015, Tavakkol 2012, van der Post 2010, Wijnen 1999). It is classified as pathogenic in ClinVar (Variation ID: 89363), and observed once in the Genome Aggregation Database general population database (1/30714 alleles). The variant introduces a frameshift, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Baglietto L et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010; 102(3):193-201. Lavoine N et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 2015; 52(11):770-8. Tavakkol Z et al. Germline mutation in MSH6 associated with multiple malignant neoplasms in a patient With Muir-Torre syndrome. J Clin Oncol. 2012; 30(22):e195-8. van der Post R et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010; 47(7):464-70. Wijnen J et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 1999; 23(2):142-4. -

Lynch syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2016	Variant summary: The MSH6 c.3261delC (p.Phe1088Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (e.g. p.Arg1172fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/120336 control chromosomes at a frequency of 0.0001745, which is approximately equal to the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). However, the variant has been reported in many HNPCC patients in the literature in heterozygous state. The variant has also been cited in homozygous and compound heterozygous states in patients with early onset cancer phenotypes (Ilencikova_PedBlodCanc_2011 and Auclair_HumMut_2007, respectively). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 06, 2023	The p.Phe1088SerfsX2 variant in MSH6 has been reported in the heterozygous state in >5 individuals with MSH6-associated cancers (Baglietto 2010 PMID: 20028993, Meric-Bernstam 2016 PMID: 26787237), and in the compound heterozygous state in 1 individual with constitutional mismatch repair deficiency syndrome (CMMRD) who also carried another MSH6 variant (Lavoine 2015 PMID: 26318770). This variant has been identified in 0.01% (1/10370) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. Furthermore, this variant was classified as Pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar Variation ID: 89363). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PVS1. -
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	Genetics and Molecular Pathology, SA Pathology	Jul 24, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This variant deletes 1 nucleotide in exon 5 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, Muir-Torre syndrome and constitutional mismatch repair deficiency syndrome (PMID: 15236168, 15483016, 17117178, 17557300, 20007843, 20487569, 20587412, 22480969, 22734033, 27064304). This variant has been identified in 1/30714 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. -

Endometrial carcinoma Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 06, 2022	_x000D_ Criteria applied: PVS1, PS4_MOD -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Feb 21, 2023	- -

Lynch syndrome 5 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 22, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 03-09-2020 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 14, 2023	Criteria applied: PVS1,PS4,PM2_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	This variant deletes 1 nucleotide in exon 5 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 and families affected with Lynch syndrome, Muir-Torre syndrome, or constitutional mismatch repair deficiency syndrome (PMID: 15236168, 15483016, 17117178, 17557300, 20007843, 20487569, 20587412, 22480969, 22734033, 27064304). This variant has been identified in 1/30714 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	Sep 17, 2021	The c.3261delC pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3261, causing a translational frameshift with a predicted alternate stop codon (p.F1088Sfs*2). This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families; several whose LS-associated tumors demonstrating high microsatellite instability and/or loss of MSH6 staining by immunohistochemistry (IHC) (Wijnen J et al. Nat. Genet. 1999 Oct;23:142-4; Kets CM et al. Br J Cancer, 2006 Dec;95:1678-82; Devlin LA et al. Ulster Med J, 2008 Jan;77:25-30; Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; van der Post RS et al. J. Med. Genet. 2010 Jul;47:464-70; Bonnet D et al. Dig Liver Dis, 2012 Jun;44:515-22; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31; Lagerstedt-Robinson K et al. Oncol Rep. 2016 Nov;36(5):2823-2835; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Ylmaz A et al. Int J Colorectal Dis, 2020 Feb;35:351-353). This mutation has also been reported in the homozygous state as well as compound heterozygous with a second mutation in MSH6 in several patients with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (Auclair J et al. Hum Mutat. 2007 Nov;28(11):1084-90; Xu M et al. Biomed Rep, 2020 Mar;12:134-138; Ando T et al. BMC Gastroenterol, 2021 Aug;21:326). 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;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 14, 2021

- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Phe1088SerfsX2 variant was identified in 15 of 6554 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Bonadona 2011, Devlin 2008, Hampel 2005, Hendriks 2004, Overbeek 2007, Plaschke 2004, Sjursen 2010). The variant was also identified in dbSNP (ID: rs267608078) “With pathogenic allele”, Clinvitae database (2x as pathogenic), InSiGHT Colon Cancer Gene Variant Database (24x as pathogenic), the ClinVar database (classified as a pathogenic variant by an expert panel), GeneInsight COGR database 1x and UMD (27x as a causal variant). The p.Phe1088SerfsX2 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1088 and leads to a premature stop codon at position 1089. 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. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Mismatch repair cancer syndrome 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Lynch-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

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

Invitae

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Phe1088Serfs*2) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10508506, 15483016, 18301448, 20007843, 20028993, 20587412, 20591884, 22734033). ClinVar contains an entry for this variant (Variation ID: 89363). For these reasons, this variant has been classified as Pathogenic. -

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: rs267608078; hg19: chr2-48030639;