chr2-47804952-CCTG-C

Position:

• chr2-47804952-CCTG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The ENST00000234420.11(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 Conflicting classifications of pathogenicity (no stars). 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 ENST00000234420.11 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.57

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in ENST00000234420.11
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000234420.11. 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140774.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3485_3487delCTG	p.Ala1162del	disruptive_inframe_deletion	6/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3485_3487delCTG	p.Ala1162del	disruptive_inframe_deletion	6/10	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 15, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 14, 2022	This variant is an in-frame deletion of an alanine in the the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with endometrial cancer, uterine, colorectal, breast cancer, and Lynch syndrome (PMID: 22658618, 28514183, 28888541, 34667028, ClinVar: SCV000172773). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Lynch syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 24, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2021

Not observed in large population cohorts (Lek 2016); In-frame deletion of 1 amino acid in a non-repeat region in the critical ATPase domain (Warren 2007, Kansikas 2011); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22658618) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

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

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: rs63751427; hg19: chr2-48032091;