rs876658650

Variant names:

• chr2-47806285-CATT-C
• rs876658650
• NM_000179.3:c.3732_3734delATT

Your query was ambiguous. Multiple possible variants found:

• chr2-47806285-CATT-C
• chr2-47806285-CATT-CATTATT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_000179.3(MSH6):​c.3732_3734delATT​(p.Leu1244del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH6 NM_000179.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 7.62

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000179.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-47806285-CATT-C is Pathogenic according to our data. Variant chr2-47806285-CATT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 231746.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3732_3734delATT	p.Leu1244del	disruptive_inframe_deletion	Exon 8 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3732_3734delATT	p.Leu1244del	disruptive_inframe_deletion	Exon 8 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 29, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3732_3734delATT variant (also known as p.L1244del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame ATT deletion between nucleotide positions 3732 and 3734 and a deletion of the leucine at codon 1244. This alteration has been identified in multiple families who meet Amsterdam Criteria for Lynch Syndrome and it segregates with disease in these families (Ambry internal data). Based on internal structural assessment, this alteration disrupts the structure of the ATPase domain (Warren JJ et al. Mol. Cell. 2007 May;26:579-92; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Aug 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of one amino acid located in the ATPase domain of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome (ClinVar SCV000750673.6, SCV000275689.6). It has been shown that this variant segregates with disease (communication with an external laboratory; ClinVar SCV000275689.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Jun 17, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944) -

Nov 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.3732_3734delATT; p.Leu1244del variant (rs876658650), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 231746). However, a nearby in-frame deletion, p.Arg1242del has been reported in individuals with colon cancer and has been classified likely pathogenic by the InSIGHT expert panel (Thompson 2014). The c.3732_3734delATT variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single leucine residue leaving the rest of the protein in-frame. Due to limited information, the clinical significance of the c.3732_3734delATT; p.Leu1244de variant is uncertain at this time. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Dec 20, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.3732_3734delATT (p.Leu1244del) results in an in-frame deletion that is predicted to remove one amino acid from the ATPase domain of the encoded protein. The variant was absent in 251206 control chromosomes. c.3732_3734delATT has been observed in individuals with a personal and family history of Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer (personal correspondence, partner laboratory). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 231746). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch syndrome Pathogenic:1

Jun 20, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple individuals with Lynch Syndrome (Ambry, Invitae internal data listed in ClinVar). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described. (PMID: 17531815) This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in more than one family (Ambry, Invitae internal data). -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3732_3734del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Leu1244del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome-related cancers (external communication, internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 231746). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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: rs876658650; hg19: chr2-48033424;