rs267608120

Positions:

• chr2-47806605-AAAGC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000179.3(MSH6):​c.3959_3962delCAAG​(p.Ala1320fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:22 O:2
• Conservation: PhyloP100: 9.28

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]

FBXO11 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PP5: Variant 2-47806605-AAAGC-A is Pathogenic according to our data. Variant chr2-47806605-AAAGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 89488.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806605-AAAGC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3959_3962delCAAG	p.Ala1320fs	frameshift_variant	9/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3959_3962delCAAG	p.Ala1320fs	frameshift_variant	9/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248908 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460866 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 726738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000459

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: 0.0000828

GnomAD4 genome Cov.: 32

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 01, 2022	The MSH6 c.3959_3962del (p.Ala1320GlufsTer6) variant results in the deletion of four nucleotides starting at position c.3959 and ending at position c.3962, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. The new stop codon is located near the three prime end of the penultimate exon and therefore nonsense-mediated mRNA decay is not expected to occur. This variant has been reported as an Ashkenazi-Jewish founder variant (PMID: 21155762). Across a selection of the available literature, the c.3959_3962del variant has been reported in at least ten patients with colorectal cancer (PMID: 15872200; PMID: 20028993; PMID: 21155762; PMID: 28944238). This variant has also been reported in patients with cancers of the endometrium (PMID: 12732731; PMID: 15098177; PMID: 26689913), breast (PMID: 30498870), and pancreas (PMID: 29922827). This variant disrupts the very last 40 amino acids of the MSH6 protein, a region that overlaps a binding site for its binding partner MSH2 (PMID: 9774676). This variant is reported in the non-cancer population of the Genome Aggregation Database in two alleles at a frequency of 0.00021 in the Ashkenazi-Jewish population (version 2.1.1). Based on the available evidence, the c.3959_3962del (p.Ala1320GlufsTer6) variant is classified as pathogenic for Lynch syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 22, 2018	This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 5 amino acids downstream of the mutation, p.Ala1320Glufs*6. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MSH6 protein with potentially abnormal function. This pathogenic sequence change has been described as an Ashkenazi Jewish founder mutation causing Lynch syndrome (Raskin L, et al., 2011; Laitman Y, et al.,2012). This patient carries this pathogenic sequence change in the MSH6 gene in his germline and has an elevated risk developing MSH6-related Lynch syndrome. Our interpretation is based on the current understanding of MSH6-related Lynch syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 02, 2021	This frameshift variant causes the premature termination of MSH6 protein synthesis. In addition, it has been reported in individuals with Lynch Syndrome and Constitutional Mismatch Repair Deficiency (CMMRD) syndrome in the published literature and is a founder mutation in the Ashkenazi Jewish population (PMIDs: 30498870 (2019), 26544533 (2016), 25430799 (2015), 24440087 (2014), 21155762 (2011), 20028993 (2010), and 12732731 (2003)). Based on the available information, this variant is classified as pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MSH6: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2022	Common founder variant in the Ashkenazi Jewish population (Cox 2018); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MSH6-related cancers (Goodfellow 2003, Raskin 2011, Goldberg 2014, DeRycke 2017); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.3956_3959delAAGC; This variant is associated with the following publications: (PMID: 12732731, 21155762, 20028993, 23206658, 25430799, 28873162, 30152102, 29946849, 26544533, 29922827, 24440087, 22219001, 26822575, 25642631, 24371622, 26823682, 25345868, 23990280, 20007843, 29485237, 30498870, 31730237, 28944238, 29625052, 32719484, 30787465, 26689913, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Lynch syndrome 5 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 12, 2018	The c.3959_3962delCAAG (p.Ala1320Glufs*6) frameshift variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome associated tumors (PMID: 15872200, 20007843, 20028993, 21155762, 23990280, 24440087). This variant is also extremely rare in the population according to gnomAD (4/243772). Therefore, the c.3959_3962delCAAG (p.Ala1320Glufs*6) variant in the MSH6 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 21, 2016	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 12-08-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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. -

Lynch syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2016	Variant summary: The MSH6 c.3959_3962delCAAG (p.Ala1320Glufs) 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. If this variant escapes NMD, it is expected to truncate P-loop containing nucleoside triphosphate hydrolase. Other similar truncations variants in this gene have been classified as pathogenic by our laboratory (e.g. p.Ala1320fs). This variant is absent in 122768 control chromosomes. This variant has been reported in literature as a pathogenic variant found in several patients with Lynch syndrome related cancers (Goodfellow_2003, Raskin_2015). It is regarded as a founder mutation in Ashkenazi Jews. Multiple clinical labs/reputable databases have classified it as pathogenic. Taken together, this variant is classified as Pathogenic. -
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	Aug 24, 2021	The p.Ala1320GlufsX6 variant in MSH6 has been reported in >15 individuals with Lynch Syndrome-associated cancers (Goodfellow 2003 PMID: 12732731, Hampel 2005 PMID: 15872200, Raskin 2011 PMID: 21155762, Goldberg 2014 PMID: 23990280, Yurgelun 2015 PMID: 25980754, Lu 2015 PMID: 26689913, DeRycke 2017 PMID: 28944238, Bernstein-Molho 2019 PMID: 30980208) and is believed to be an Ashkenazi Jewish founder variant (Raskin 2011 PMID: 21155762). It has also been reported in the compound heterozygous state in two families with constitutional mismatch repair deficiency CMMRD) syndrome (CMMRD), where the variant was identified in trans with a second pathogenic variant in MSH6 (Bakry 2014 PMID: 24440087, Shapira Rootman 2020 PMID: 31730237). Additionally, this variant segregated with CMMRD in 2 affected siblings (Bakry 2014 PMID: 24440087). This variant has been identified in 0.03% (3/10024) of Ashkenazi Jewish chromosomes and in 0.009% (1/112292) 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 1320 and leads to a premature termination codon 6 amino acids downstream. This termination codon occurs within the terminal 50 bases of the penultimate exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing less than 3% of the coding region, with 34 amino acids removed. Tumors from two patients with this variant have been found to have loss of MSH6 protein expression (Raskin 2011 PMID: 21155762, Bakry 2014 PMID: 24440087). Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with autosomal dominant Lynch syndrome. Additionally, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89488). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch Syndrome (ACMG/AMP Criteria applied: PS4, PS3_Moderate, PVS1_Moderate, PM2_Supporting) and autosomal recessive CMMRD (ACMG/AMP Criteria applied: (PM3_Strong, PVS1_Moderate, PS3_Moderate, PP1_Moderate, PM2_Supporting). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 29, 2024	This variant deletes 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to impact the ATPase domain and the MSH2 binding domain. This variant has been reported in individuals affected with Lynch syndrome, as well as individuals affected with colorectal/endometrial cancers where some also displayed clinical features of Lynch syndrome (PMID: 20028993, 21155762, 22219001, 23990280, 25430799), constitutional mismatch repair syndrome (PMID: 24440087, 26544533), or breast cancer (PMID: 30498870, 33471991). This variant has been identified in 4/248908 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. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 13, 2022	The c.3959_3962delCAAG pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a deletion of 4 nucleotides at nucleotide positions 3959 to 3962, causing a translational frameshift with a predicted alternate stop codon (p.A1320Efs*6). This mutation has been reported as an Ashkenazi Jewish founder mutation for Lynch syndrome (Raskin L et al. Clin. Genet. 2011 Jun:79:512-22; Goldberg Y et al. Fam. Cancer. 2014 Mar;13:65-73). It has been identified in numerous individuals with Lynch syndrome tumors, including several with tumors demonstrating microsatellite instability and/or absent MSH6 on IHC (Goodfellow PJ et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100:5908-13; Hampel H et al. N. Engl. J. Med. 2005 May;352:1851-60; Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201). In addition, the international consortium of childhood constitutional mismatch repair deficiency (CMMRD) reported this deletion in three individuals with CMMRD: one with GI polyposis, one with T-cell lymphoma and GI polyposis, and one with glioblastoma multiforme (Bakry D et al. Eur. J. Cancer. 2014 Mar;50:987-96). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2022	This variant deletes 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to impact the ATPase domain and the MSH2 binding domain. This variant has been reported in individuals affected with Lynch syndrome or colorectal/endometrial cancers along with clinical features of Lynch syndrome (PMID: 20028993, 21155762, 22219001, 23990280, 25430799), constitutional mismatch repair syndrome (PMID: 24440087, 26544533), or breast cancer (PMID: 30498870). This variant has been identified in 4/248908 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	curation	Sema4, Sema4	Mar 02, 2022	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.3959_3962delCAAG deletion variant was identified in 7 of 6956 proband chromosomes (frequency: 0.001) from Israeli individuals with familial and sporadic gastric and pancreatic cancers, and both Ashkenazi Jewish(AJ) and non-AJ individuals or families with endometrial and colorectal cancers, unselected for family history and age at diagnosis; and was not identified in 3310 control chromosomes from healthy individuals (Goodfellow 2003, Hampel 2005, Hampel 2005, Raskin 2010, Laitman 2012). The variant was also found in 3/32 patients from 14 kindreds with CMMRD (Constitutional Mismatch Repair Deficiency), a cancer predisposition syndrome in children characterized by homozygous/biallelic MMR gene mutations and the development of hematological, brain and gastrointestinal cancers; co-occurring with c.3984_3987dup mutation (Bakry 2014). Raskin (2010) identified the c.3959_3962delCAAG variant as a founder mutation causing Lynch syndrome in the AJ population. A study looking at penetrance and expressivity of pathogenic germline MSH6 mutations which included this variant, showed that patients carrying these mutations were at increased risk of cancer (specific tumour spectrum undefined), with 58% penetrance, and later onset than that seen in MSH2 or MLH1 mutant carriers (Buttin 2004). The variant was also identified in HGMD, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as a pathogenic variant by Insight, and reviewed by an expert panel as pathogenic), and UMD (10X as a causal variant). The p.Ala1320GlufsX6 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1320 and leads to a premature stop codon 6 codons downstream. 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. -

Inherited MMR deficiency (Lynch syndrome) Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Jun 18, 2024

PVS1_Moderate,PS4_Very Strong,PM3_Supporting,PP4 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change creates a premature translational stop signal (p.Ala1320Glufs*6) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs267608119, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of MSH6-related conditions (PMID: 12732731, 20007843, 20028993, 21155762, 23990280, 24440087, 25430799, 26544533). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 21155762). This variant is also known as 3956_3959delAAGC. ClinVar contains an entry for this variant (Variation ID: 89488). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762, 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

Feb 19, 2024

- -

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)		0.050		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: rs267608120; hg19: chr2-48033744;