chr2-47800814-TAA-T

Variant names:

• chr2-47800814-TAA-T
• rs730881827
• NM_000179.3:c.2832_2833delAA

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.2832_2833delAA​(p.Ile944MetfsTer4) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 2.54

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 2-47800814-TAA-T is Pathogenic according to our data. Variant chr2-47800814-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 182680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.2832_2833delAA	p.Ile944MetfsTer4	frameshift_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.2832_2833delAA	p.Ile944MetfsTer4	frameshift_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Sep 03, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with ovarian cancer, endometrial cancer, and/or colorectal polyps (Susswein 2016, Lilyquist 2017); This variant is associated with the following publications: (PMID: 28888541, 26681312, 30787465) -

Apr 19, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of MSH6 protein synthesis. It has been reported in women affected with endometrial and ovarian cancer in the published literature (PMID: 26681312 (2015), 28888541 (2017)). Based on the available information, this variant is classified as pathogenic. -

Lynch syndrome 5 Pathogenic:2

Mar 28, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 05, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 25, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2832_2833delAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 2832 to 2833, causing a translational frameshift with a predicted alternate stop codon (p.I944Mfs*4). This mutation has been identified in several cohorts of individuals who underwent multigene panel testing for hereditary cancer risk, including patients with a personal diagnosis of endometrial and breast cancer (Susswein LR et al. Genet Med, 2016 08;18:823-32; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Roberts ME et al. Genet Med, 2018 10;20:1167-1174). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. -

May 30, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides 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 two individuals affected with endometrial cancer, one of whom was also affected with colon polyps (PMID: 26681312, 29345684), and in one individual affected with breast cancer (PMID: 29345684). 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. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Nov 07, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.2832_2833delAA (p.Ile944MetfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250456 control chromosomes. c.2832_2833delAA has been reported in the literature in at least one individual affected with endometrial cancer and colon polyps (e.g. Susswein_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182680). Based on the evidence outlined above, the variant was classified as pathogenic. -

MSH6-related disorder Pathogenic:1

May 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.2832_2833delAA variant is predicted to result in a frameshift and premature protein termination (p.Ile944Metfs*4). This variant was reported in an individual with Lynch Syndrome spectrum cancers and individuals undergoing cancer genetic testing (Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541; Table S2, Roberts et al. 2018. PubMed ID: 29345684; Table A2, Espenschied et al. 2017. PubMed ID: 28514183). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/182680/). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jul 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ile944Metfs*4) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with endometrial cancer and colon polyps (PMID: 26681312). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 182680). For these reasons, this variant has been classified as Pathogenic. -

Endometrial carcinoma Pathogenic:1

Apr 13, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs730881827; hg19: chr2-48027953;