rs63751408

Positions:

• chr2-47800623-TG-TAAAA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_000179.3(MSH6):​c.2641delinsAAAA​(p.Gly881delinsLysSer) variant causes a protein altering 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G881G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 protein_altering
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 2.38

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.2641delinsAAAA	p.Gly881delinsLysSer	protein_altering_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.2641delinsAAAA	p.Gly881delinsLysSer	protein_altering_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 08, 2015	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2021	Published functional studies demonstrate no damaging effect: ability to dimerize with MSH2 and mismatch repair (MMR) activity similar to wild type in an in vitro MMR assay (Kariola 2004); In-frame deletion of 1 amino acid and insertion of 2 amino acids in a non-repeat region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Observed in individual with a personal history of endometrial cancer (Hampel 2006); This variant is associated with the following publications: (PMID: 16885385, 15354210, 21120944, 28873162) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 23, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 10, 2024	The c.2641delGinsAAAA variant (also known as p.G881delinsKS), located in coding exon 4 of the MSH6 gene, results from an in-frame deletion of one nucleotide and insertion of four nucleotides at position 2641. This results in the deletion of a glycine residue at codon 881 and insertion of a lysine and serine residue. This amino acid position is poorly conserved in available vertebrate species. This alteration has been reported in an individual diagnosed with endometrial cancer at age 83 whose tumor displayed high microsatellite instability (MSI-H) with absent MLH1 protein expression and positive MSH2/MSH6 protein expression by immunohistochemistry (IHC); MLH1 promoter methylation studies also showed hypermethylation (Kariola R et al. Br J Cancer. 2004 Oct 4;91(7):1287-92; Hampel H et al. Cancer Res. 2006 Aug;66:7810-7). In a functional study, this variant demonstrated relative mismatch repair activity similar to wild type MSH6 in an in vitro complementation assay and interaction with MSH2 remained intact (Kariola R et al. Br J Cancer. 2004 Oct 4;91(7):1287-92). In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2024	This variant causes the deletion of a glycine and insertion of lysine and serine at codon 881 in the MSH6 protein. Functional studies have shown that this variant does not impact MSH6 mismatch repair activity, protein expression, or binding to MSH2 (PMID: 15354210, 21120944). This variant has been reported in an individual affected with endometrial cancer (PMID: 15354210, 16885385) 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2017

This sequence change deletes one nucleotide and inserts 4 nucleotides in exon 4 of the MSH6 mRNA (c.2641delGinsAAAA). This leads to the replacement of glycine with lysine and the insertion of an additional serine amino acid residue in the MSH6 protein (p.Gly881delinsLysSer) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with endometrial cancer (PMID: 15354210, 16885385). ClinVar contains an entry for this variant (Variation ID: 89305). Experimental studies have shown that this variant does not impact MSH6 mismatch repair activity or its ability to bind MSH2 (PMID: 15354210). In summary, this variant is a rare in-frame insertion that has been shown to not affect protein function in vitro. It has been reported in an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2023

This variant, c.2641delinsAAAA , is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the MSH6 protein (p.Gly881delinsLysSer). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with endometrial cancer (PMID: 15354210). ClinVar contains an entry for this variant (Variation ID: 89305). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant does not substantially affect MSH6 function (PMID: 15354210, 21120944). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Endometrial carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63751408; hg19: chr2-48027763;