2-47804952-CCTG-C

Variant names:

• chr2-47804952-CCTG-C
• rs63751427
• NM_000179.3:c.3485_3487delCTG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000179.3(MSH6):​c.3485_3487delCTG​(p.Ala1162del) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1162A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.57
• Publications: 1 publications found

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]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 51 uncertain in NM_000179.3
• 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 2-47804952-CCTG-C is Pathogenic according to our data. Variant chr2-47804952-CCTG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 140774.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.3485_3487delCTG	p.Ala1162del	disruptive_inframe_deletion	Exon 6 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3485_3487delCTG	p.Ala1162del	disruptive_inframe_deletion	Exon 6 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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 15, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3485_3487delCTG variant (also known as p.A1162del) is located in coding exon 6 of the MSH6 gene. This variant results from an in-frame CTG deletion at nucleotide positions 3485 to 3487. This results in the in-frame deletion of an alanine at codon 1162. This alteration has been identified in three individuals with endometrial cancer and ages at diagnosis ranged from 45y to 54y. One of the individuals was also diagnosed with rectal cancer at the age of 60y. Tumor results for two of the individuals revealed loss of MSH6 protein expression on immunohistochemistry (IHC) while the third individual had a family history that met Amsterdam criteria (Ambry internal data). The alteration was also reported in a patient with endometrial cancer and rectal cancer diagnosed at the ages of 53y and 61y, respectively. Furthermore, tumor results from the endometrial cancer revealed microsatellite instability (MSI-H) (Goodfellow PJ et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10: 5908-13). This alteration has also been reported in an individual with a personal history of uterine and breast cancers, and family history of uterine, colon and breast cancers (Schwartz CJ et al. Clin Cancer Res, 2022 Jan;28:404-413). The alanine residue resides in a well-defined functional domain and is adjacent to a helix that contains the MSH6 ATP binding p-loop (Warren JJ et al. Mol. Cell 2007 May;26(4):579-92). This amino acid position is highly conserved in available vertebrate species and the impacted region is critical for protein function (Ambry internal data). 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. -

Jan 23, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is an in-frame deletion of an alanine at codon 1162 in the ATPase domain of the MSH6 protein. To our knowledge, functional studies have not been published for this variant. This variant is reported to disrupt protein structure and impact function (ClinVar: SCV004185562.1). This variant has been reported in individuals affected with endometrial cancer, uterine, colorectal, breast cancer, and Lynch syndrome, with multiple tumors demonstrating loss of MSH6 protein via immunohistochemistry and/or high microsatellite instability (PMID: 22658618, 28514183, 28888541, 34667028; ClinVar: SCV000172773.10, SCV000624874.5). However, an individual affected with uterine cancer had tumor data demonstrating microsatellite stability and intact MSH6 protein (PMID: 34667028). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A missense variant affecting codon 1162, c.3485C>A (p.Ala1162Asp), is considered to be disease-causing (ClinVar variation ID: 127587), suggesting that this position is important for the protein function. Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Lynch syndrome 5 Pathogenic:1

Aug 24, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -

not provided Pathogenic:1

Jun 12, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid(s) with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 22658618, 12732731, 23056405, 17531815, 28888541, 28514183, 34667028, Plazzer2024[preprint], 21120944) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3485_3487del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Ala1162del), 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 (PMID: 22658618, 28514183; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 140774). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Ala1162Asp) have been determined to be pathogenic (Invitae). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63751427; hg19: chr2-48032091;