2-47798717-TAAAA-TAAA

Position:

• chr2-47798717-TAAAA-TAAA

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.741delA​(p.Lys247fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.0430

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]

MSH6 (HGNC:):

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 2-47798717-TA-T is Pathogenic according to our data. Variant chr2-47798717-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 237213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47798717-TA-T is described in Lovd as [Pathogenic]. Variant chr2-47798717-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.741delA	p.Lys247fs	frameshift_variant	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.741delA	p.Lys247fs	frameshift_variant	4/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74094

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2015	This sequence change deletes 1 nucleotide from exon 4 of the MSH6 mRNA (c.741delA), causing a frameshift at codon 247. This creates a premature translational stop signal (p.Lys247Asnfs*32) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in a germline sample in the literature, truncating variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This variant deletes 1 nucleotide in exon 4 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 an individual affected with endometrioid carcinoma that exhibited microsatellite instability and loss of MLH1, PMS2, and MSH6 proteins by immunohistochemistry analyses (PMID: 26099011). This variant has been identified in 1/31128 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:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 23, 2022	The c.741delA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 741, causing a translational frameshift with a predicted alternate stop codon (p.K247Nfs*32). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 26, 2023	This variant deletes 1 nucleotide in exon 4 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 an individual affected with endometrioid carcinoma that exhibited microsatellite instability and loss of MLH1, PMS2, and MSH6 proteins by immunohistochemistry analyses (PMID: 26099011). This variant has been identified in 1/31128 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 10, 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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 28, 2023

The MSH6 c.741del; p.Lys247AsnfsTer32 variant (rs267608041) is reported in the literature in two individuals affected with Lynch syndrome (Graham 2015, Pearlman 2019). This variant is also reported in ClinVar (Variation ID: 237213). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Graham RP et al. Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am J Surg Pathol. 2015 Oct;39(10):1370-6. PMID: 26099011. Pearlman R et al. Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome. J Med Genet. 2019 Jul;56(7):462-470. PMID: 30877237. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 237213). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 26099011). This variant is present in population databases (rs267608041, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Lys247Asnfs*32) 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). -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Lys247AsnfsX32 variant was identified in sporadic gastric and lynch syndrome suspected tumours as a somatic event (and not germline) in 4 of 176 proband chromosomes (frequency: 0.02) from Portuguese and Spanish individuals or families (Pinto 2008, Vargas-Parra 2017). The variant was also identified in dbSNP (ID: rs267608041) “With Pathogenic allele”, ClinVar (classified pathogenic by Invitae), Cosmic (3x in stomach carcinoma), Insight Colon Cancer Gene Variant Database (1x), Mismatch Repair Genes Variant Database (2x). The variant was not identified in Genesight-COGR, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.741delA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 247 and leads to a premature stop codon 32 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 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. -

Endometrial carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 23, 2023

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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: rs267608041; hg19: chr2-48025856;