rs63751319

chr2-47806489-AGGAGACT-A

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.3840_3846del(p.Glu1281LeufsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,818 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. Q1280Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.97

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 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 2-47806489-AGGAGACT-A is Pathogenic according to our data. Variant chr2-47806489-AGGAGACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 89474.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47806489-AGGAGACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3840_3846del	p.Glu1281LeufsTer44	frameshift_variant	9/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3840_3846del	p.Glu1281LeufsTer44	frameshift_variant	9/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461818 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727214

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 5 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 25, 2016	- -
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: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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2017	Variant summary: The MSH6 c.3840_3846delGGAGACT (p.Glu1281Leufs) 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.3938_3941dupTTCA, p.Gln1314fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120874 control chromosomes and has been reported in at least 2 affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2023	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; Observed in individuals with MSH6-related cancers (Barnetson et al., 2006; Devlin et al., 2008; Baglietto et al., 2010; Pearlman et al., 2019); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as Q1280fsX1324; This variant is associated with the following publications: (PMID: 16807412, 20028993, 30877237, 18269114, 30787465) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 23, 2021	This frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported in patients with Lynch Syndrome in the published literature (PMIDs: 16807412 (2006), 18269114 (2008), 20028993 (2010), 26666765 (2015), and 30877237 (2019)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 22, 2021	This variant deletes 7 nucleotides in exon 9 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 colorectal cancer (PMID: 16807412), individuals affected with Lynch syndrome or colorectal cancer and clinical features of Lynch syndrome (PMID: 18269114, 26666765). 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	clinical testing	Ambry Genetics	Mar 17, 2022	The c.3840_3846delGGAGACT pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a deletion of 7 nucleotides at nucleotide positions 3840 to 3846, causing a translational frameshift with a predicted alternate stop codon (p.E1281Lfs*44). This mutation has been reported in a 44-year-old female with transverse colon cancer who met Bethesda guidelines for testing (Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63), as well as in an individual from a cohort of patients described as HNPCC-like due to clustering of HNPCC-related cancers or early age of diagnosis (Devlin LA et al. Ulster Med. J. 2008 Jan;77:25-30). This mutation was also observed in a patient with MSH6-absent colorectal cancer (Haraldsdottir S et al. Fam. Cancer. 2016 Apr;15:253-60). 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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change creates a premature translational stop signal (p.Glu1281Leufs*44) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the MSH6 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (Lynch syndrome) (PMID: 16807412, 18269114, 20028993). ClinVar contains an entry for this variant (Variation ID: 89474). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Ala1320Glufs*6) have been determined to be pathogenic (PMID: 21155762). 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. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The MSH6 p.Glu1281Leufs*44 variant was identified in 3 of 2216 proband chromosomes (frequency: 0.001) from individuals or families with colorectal or endometrial cancer, or Lynch syndrome (Baglietto 2010, Barnetson 2006, Devlin 2008). The variant was also identified in dbSNP (ID: rs63751319 as "With Pathogenic allele"), ClinVar (5x as pathogenic by InSight, GeneDx, Invitae, Ambry Genetics, and Integrated Genetics/Laboratory Corporation of America and 1x as likely pathogenic by Counsyl), COGR, and Insight Hereditary Tumors databases. The variant was not identified in Cosmic, MutDB, UMD-LSDB, Zhejiang University Database, the Mismatch Repair Genes Variant database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3840_3846del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1281 and leads to a premature stop codon at position 1324. This alteration is 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 MSH6-associated cancers 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. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 07, 2023

- -

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: rs63751319; hg19: chr2-48033628;