chr2-47806630-A-ATCAG

Position:

• chr2-47806630-A-ATCAG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000179.3(MSH6):​c.3984_3987dupGTCA​(p.Leu1330fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,412 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: 0.0000041 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:21 O:1
• Conservation: PhyloP100: 0.0240

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 10 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. Fraction of 0.0233 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 2-47806630-A-ATCAG is Pathogenic according to our data. Variant chr2-47806630-A-ATCAG is described in ClinVar as [Pathogenic]. Clinvar id is 89496.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.3984_3987dupGTCA	p.Leu1330fs	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.3984_3987dupGTCA	p.Leu1330fs	frameshift_variant	9/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246806 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459412 Hom.: 0 Cov.: 35 AF XY: 0.00000551 AC XY: 4 AN XY: 726112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The MSH6 c.3984_3987dup; p.Leu1330ValfsTer12 variant (rs267608121) is reported in the literature in numerous heterozygous individuals affected with Lynch syndrome and in homozygous or compound heterozygous individuals with constitutional mismatch repair syndrome (Raskin 2011, Diaz-Velasquez 2023, Levi 2015). This variant is recognized as a founder variant in the Ashkenazi Jewish population (Raskin 2011). This variant is reported in ClinVar (Variation ID: 89496) and is found in the Ashkenazi Jewish population with an allele frequency of 0.03% (3/34406 alleles) in the Genome Aggregation Database. This variant causes a frameshift by inserting four nucleotides, resulting in a truncated protein. Based on available information, this variant is considered to be pathogenic. References: Raskin L et al. Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. Clin Genet. 2011 Jun;79(6):512-22. PMID: 21155762. Diaz-Velasquez CE et al. Evaluation of genetic alterations in hereditary cancer susceptibility genes in the Ashkenazi Jewish women community of Mexico. Front Genet. 2023 Feb 10;14:1094260. PMID: 36845387. Levi Z et al. The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer. Clin Genet. 2015 Nov;88(5):474-8. PMID: 25307252. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2020	Frameshift variant predicted to result in protein truncation as the last 31 amino acids are lost and replaced with 11 incorrect amino acids; Observed in the heterozygous state in individuals with a personal or family history of cancer consistent with pathogenic variants in this gene and considered an Ashkenazi Jewish founder variant (Peterlongo 2003, Goldberg 2010, Raskin 2011, Salo-Mullen 2015, Cox 2018, Lee 2018); Case control studies suggest this variant is associated with colon and endometrial cancer (Raskin 2011); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3987insGTCA and 3987ins4; This variant is associated with the following publications: (PMID: 28514183, 29144512, 30152102, 22219001, 12454801, 21155762, 19851887, 14520694, 26822575, 25642631, 26544533, 26440929, 25307252, 26681312, 29485237, 30498870, 30077346, 24440087, 30702970, 30322717, 31730237, 29625052, 26689913, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 05, 2017	DNA sequence analysis of the MSH6 gene demonstrated a four base pair duplication in exon 9, c.3984_3987dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 11 amino acids downstream of the mutation, p.Leu1330Valfs*12. 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 is considered an Ashkenazi Jewish founder mutation (Goldberg et al. 2010, Raskin et al. 2011) and has previously been found to segregate in several families with colorectal, endometrial, and pancreatic cancer (Peterlongo et al. 2003, Hendriks et al. 2004, Hegde et al. 2005, Salo-Mullen et al. 2015) and in the compound heterozygous state in individuals with constitutional mismatch repair deficiency syndrome (Bakry et al. 2014). This patient has an increased risk of colorectal, endometrial and pancreatic cancers and other MSH6-related cancers. The contribution of this variant to this patient's throat/lung cancer and pancytopenia remains uncertain. Heterozygous pathogenic variants in MSH6 are associated with Lynch syndrome, which is associated with an increased risk of certain cancers, particularly colon and endometrial cancers [OMIM#614350, 608089]. Leukemia and other hematological malignancies can be an unusual presentation of Lynch syndrome (Yu VP, et al., 2009; Bansidhar BJ, 2012). Homozygous or compound heterozygous pathogenic variants in MSH6 lead to a mismatch repair deficiency which is a rare childhood cancer predisposition syndrome with 4 main tumor types: hematologic malignancies, brain/central nervous system tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma [OMIM#276300]. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2022	This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. In the published literature, the variant has been reported as an Ashkenazi Jewish founder mutation and is found in families with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 14520694 (2003), 15236168 (2004), 19851887 (2010), 21155762 (2011)), pancreatic cancer (PMID: 26440929 (2015)), endometrial cancer (PMID: 26681312 (2015)), glioblastoma (PMID: 29625052 (2018)), ovarian cancer (PMID: 30322717 (2018)), and breast cancer (PMID: 30498870 (2019)). This variant has also been found in a compound heterozygous state in individuals with constitutional mismatch repair deficiency syndrome (CMMRD) (PMID: 24440087 (2014), 25307252 (2015)). Based on the available information, this variant is classified as pathogenic. -

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2017	Variant summary: The MSH6 c.3984_3987dupGTCA (p.Leu1330Valfs) 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. c.3991C>T, p.Arg1331X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/123518 control chromosomes at a frequency of 0.0000324, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported in numerous patients and families in the literature, including several compound heterozygotes with CMMRD. The variant has been described in the literature as an Ashkenazi Jewish founder mutation. 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	May 17, 2019	The p.Leu1330ValfsX12 (c.3984_3987dupGTCA) variant in MSH6 has been described as an Ashkenazi Jewish founder variant. It has been in the heterozygous state in over 15 individuals with Lynch syndrome associated cancers and segregated with disease in over 12 affected family members from at least 3 families (Goldberg 2010, Raskin 2011). This variant was shown to be associated with loss of expression of the MSH6 protein in the tumor tissue (Goldberg 2010). Additionally, it has been reported in at least 4 individuals with constitutional mismatch repair deficiency in the compound heterozygous state with another pathogenic MSH6 variant (Bakry 2014, Levi 2015). Additionally, this variant has been identified in 3/9998 of Ashkenazi Jewish 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 1330 and leads to a premature termination codon 12 amino acids downstream. This termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Moreover, this variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108179.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PVS1_Strong, PP1_strong, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 03, 2024	This variant inserts 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported as a recurring mutation in Ashkenazi Jews (PMID: 19851887, 21155762) and has been observed in many individuals affected with Lynch syndrome-associated cancers (PMID: 14520694, 15236168, 16237223, 19851887, 21155762, 26440929, 30498870, 34086170). This variant has also been reported in the compound heterozygous state with a second MSH6 mutation in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 24440087). This variant has been identified in 3/246806 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. -

Lynch syndrome 5 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 08, 2017	This c.3984_3987dup variant in the MSH6 gene has been reported in one HNPCC patient (PMID16237223), two endometrial cancer patients (PMID15236168) and three related CRC patients with segregation in two generations (PMID14520694). In addition, a case control study identified this variant in 8/2685 CRC cases, 2/337 endometrial cancer cases and 1/330 control. PMID19851887 suggest this variant to be a founder variant for Ashkenazi Jews. This variant is predicted to cause a frameshift and create a premature stop codon. Based upon above evidence, this c.3984_3987dupGTCA variant in the MSH6 gene is classified pathogenic. -
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	Nov 28, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 20, 2022	This variant inserts 4 nucleotides in exon 9 of the MSH6 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant has been reported as a recurring mutation in Ashkenazi Jews (PMID: 19851887, 21155762) and has been observed in many individuals affected with Lynch syndrome-associated cancers (PMID: 14520694, 15236168, 16237223, 19851887, 21155762, 26440929, 26681312, 30498870, 34086170). This variant has also been reported in the compound heterozygous state with a second MSH6 mutation in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 24440087). This variant has been identified in 3/246806 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	Oct 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 16, 2024	The c.3984_3987dupGTCA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of GTCA at nucleotide position 3984, causing a translational frameshift with a predicted alternate stop codon (p.L1330Vfs*12). This mutation is a founder mutation in the Ashkenazi Jewish population (Raskin L et al. Clin. Genet. 2011 Jun;79(6):512-22), and was reported in 19 members of four unrelated Ashkenazi Jewish families affected with colon, endometrial, gastric, ovarian, urinary and breast cancers (Goldberg Y et al. Fam. Cancer. 2010 Jun;9(2):141-50). This mutation (designated as 3987ins4) was also identified in an individual with Ashkenazi Jewish ancestry who was diagnosed with pancreatic cancer (Salo-Mullen EE et al. Cancer. 2015 Dec 15;121(24):4382-8). In addition, this mutation has been reported in multiple patients with constitutional mismatch repair deficiency (CMMR-D) syndrome (Bakry D et al. Eur. J. Cancer. 2014 Mar;50(5):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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1_Moderate+PS4+PP1_Strong -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Leu1330Valfs*12 variant was identified in 16 of 7108 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, or endometrial or pancreatic cancer and was present in 1 of 6988 control chromosomes (frequency: 0.0002) from healthy individuals (Peterlongo 2003, Raskin 2011, Salo-Mullen 2015, Barak 2010). The variant was also identified in dbSNP (ID: rs751033488) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seven other submitters) and the Insight Colon Cancer Gene Variant Database (as class 5: pathogenic). The variant was not identified in UMD-LSDB nor was it identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant has been described in the literature as a founder mutation in the Ashkenazi Jewish population (Goldberg 2010, Raskin 2011) and has also been identified as co-occurring with a pathogenic MSH6 variant (c.3959delCAAG, p.Ala1320Glufs*6) in multiple individuals with constitutional mismatch repair deficiency (Bakry 2014). The c.3984_3987dup variant is predicted to cause a frameshift which alters the protein's amino acid sequence beginning at codon 1330 and leads to a premature stop codon 12 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 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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change creates a premature translational stop signal (p.Leu1330Valfs*12) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs751033488, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome or constitutional mismatch repair deficiency syndrome (PMID: 14520694, 15236168, 16237223, 19851887, 21155762, 24440087, 26440929). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 19851887, 21155762). This variant is also known as 3987ins4. ClinVar contains an entry for this variant (Variation ID: 89496). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 09, 2023

- -

Lynch syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608121; hg19: chr2-48033769;