2-47800623-TG-TAAAA

Variant names:

• chr2-47800624-G-AAAA
• rs63751408
• NM_000179.3:c.2641delGinsAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_000179.3(MSH6):​c.2641delGinsAAAA​(p.Gly881delinsLysSer) variant causes a missense, disruptive inframe insertion 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G881D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense, disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 2.38
• Publications: 2 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: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.2641delGinsAAAA	p.Gly881delinsLysSer	missense_variant, disruptive_inframe_insertion	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.2641delGinsAAAA	p.Gly881delinsLysSer	missense_variant, disruptive_inframe_insertion	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 5 Uncertain:2

Mar 29, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 08, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Uncertain:2

Jan 23, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid and insertion of 2 amino acids in a non-repeat region; Observed in individual with a personal history of endometrial cancer (PMID: 16885385); 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 (PMID: 15354210); In silico analysis supports a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21120944, 28873162, 16885385, 17531815, 15354210) -

Hereditary cancer-predisposing syndrome Uncertain:2

Mar 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 31, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the replacement of glycine at codon 881 with novel lysine and serine residues 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. -

not specified Uncertain:1

Mar 03, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.2641delinsAAAA (p.Gly881delinsLysSer) results in an in-frame deletion-insertion that is predicted to delete 1 amino acid from the protein and inser 2 different amino acids. The variant was absent in 250448 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2641delinsAAAA has been reported in the literature in individuals affected with endometrial cancer or prostate cancer without strong evidence of causality (e.g. Kariola_2004, Mondschein_2022). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an MMR assay (Kariola_2004). The following publications have been ascertained in the context of this evaluation (PMID: 15354210, 21120944, 35892882). ClinVar contains an entry for this variant (Variation ID: 89305). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome Uncertain:1

Jan 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Endometrial carcinoma Uncertain:1

Feb 21, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

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

Other links and lift over

dbSNP: rs63751408; hg19: chr2-48027763;