rs587779297

Positions:

• chr2-47806603-GA-G
• chr2-47806603-GA-GAA
• chr2-47806603-GA-GAAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000234420.11(MSH6):​c.3957del​(p.Ala1320GlnfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1318R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 ENST00000234420.11 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 62 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47806603-GA-G is Pathogenic according to our data. Variant chr2-47806603-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 428325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47806603-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3957del	p.Ala1320GlnfsTer7	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.3957del	p.Ala1320GlnfsTer7	frameshift_variant	9/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 28, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2018

This deletion of one nucleotide in MSH6 is denoted c.3957delA at the cDNA level and p.Ala1320GlnfsX7 (A1320QfsX7) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAA[delA]GCAA. The deletion causes a frameshift which changes an Alanine to a Glutamine at codon 1320, and creates a premature stop codon at position 7 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature as a germline variant, it is predicted to cause loss of normal protein function through protein truncation. Even though nonsense-mediated decay is not expected to occur, due to the position of the variant, it is significant as the last 41 amino acids are lost and replaced with 6 incorrect amino acids. The disrupted region at the end of the gene is located within the binding site of MSH2 in the ATPase domain (Kariola 2002, Warren 2007, Kansikas 2011). Based on currently available evidence, we consider this deletion to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change creates a premature translational stop signal (p.Ala1320Glnfs*7) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 428325). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 14520694, 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2020

The c.3957delA pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a deletion of one nucleotide at position 3957, causing a translational frameshift with a predicted alternate stop codon (p.A1320Qfs*7). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of MSH6, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 41 amino acids of the protein. But based on internal data, another downstream truncating mutation (p.R1331*) has been classified as pathogenic and was reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, which indicates the importance of this region (Plaschke J et al. Eur J Hum Genet. 2006;14(5):561-6; Sjursen W, J. Med. Genet. 2010 Sep; 47(9):579-85; van Lier MG, J. Pathol. 2012 Apr; 226(5):764-74). 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 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587779297; hg19: chr2-48033742;