rs267608079

Positions:

• chr2-47798849-GC-AA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000179.3(MSH6):​c.866_867delGCinsAA​(p.Gly289Glu) variant causes a missense 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:5
• Conservation: PhyloP100: 1.94

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-47798849-GC-AA is Benign according to our data. Variant chr2-47798849-GC-AA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89572.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=9}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.866_867delGCinsAA	p.Gly289Glu	missense_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.866_867delGCinsAA	p.Gly289Glu	missense_variant		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: Uncertain:11 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2016	The p.Gly289Glu variant in MSH6 has been classified as a variant of uncertain si gnificance on September 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (Cl inVar SCV000108262.2). It has been reported in 2 individuals with Lynch syndrome associated tumors (Colley 2005, Devlin 2008) and is present in 4/66588 of Europ ean chromosomes in the Exome Aggregation Consortium database (ExAC, http://exac. broadinstitute.org, note that the ExAC database reports this variant as 2 separa te substitutions in cis, c.866G>A [rs267608079] and c.867C>A [rs267608047]). Com putational prediction tools and conservation analysis are limited or unavailable for this variant. In summary, the clinical significance of the p.Gly289Glu vari ant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 15, 2021	DNA sequence analysis of the MSH6 gene demonstrated a deletion and insertion of two base pairs in exon 4, c.866_867delinsAA. This in-frame deletion/insertion results in a missense change, p.Gly289Glu. This sequence change has been identified in individuals with colorectal cancer or suspected Lynch syndrome (PMID: 16010685, 20028993, 18269114). This sequence change has been reported in the gnomAD database with a frequency of 0.02% in the non-Finnish European subpopulation (dbSNPs rs368318845, rs267608047 ). The p.Gly289Glu change affects a poorly conserved amino acid residue located in a domain of the MSH6 protein that is known to be functional. The p.Gly289Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly289Glu change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2024	Variant summary: MSH6 c.866_867delinsAA (p.Gly289Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele (comprised of 2 individual constituent variants 2-48025989-C-A and 2-48025988-G-A in cis; GRC37 hg19) was found at a frequency of 8.5e-05 in 282558 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). c.866_867delinsAA has been reported in the literature in individuals affected with HNPCC, colorectal adenomas, colorectal cancer and breast cancer (example, Colley_2005, Devlin_2008, Baglietto_2010, Caminsky_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. At-least two co-occurrences with pathogenic variants have been observed internally (APC c.4987G>T, p.Glu1663X; CHEK2 c.1555C>T, p.Arg519X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20028993, 26898890, 16010685, 18269114, 31422818, 26333163, 23621914). ClinVar contains an entry for this variant (Variation ID: 89572). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	This variant is associated with the following publications: (PMID: 26898890, 16010685, 18269114, 23621914, 20028993, 26333163, 26635394) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 14, 2024	The MSH6 c.866_867delinsAA (p.Gly289Glu) variant has been reported in the published literature in in individuals with Lynch syndrome (PMID: 20028993 (2010), 18269114 (2008)), breast cancer (PMID: 26898890 (2016)), and colorectal adenomas (PMID: 16010685 (2005)). In a large-scale breast cancer association study, this variant has been observed in breast cancer cases and reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.00043 (22/50668 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 05, 2023	- -

Lynch syndrome 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Lynch syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Gly289Glu variant has been previously reported in the literature in 2/880 proband chromosomes. One individual had multiple colorectal adenomas and the other had HNPCC (Colley 2005, Devlin 2008). However, race-matched population controls were not sequenced in these studies and so it is possible that the full spectrum of benign variation has not yet been defined for this gene, and this variant may be benign. This variant was identified by our laboratory in one individual who had normal IHC for MSH6 and was microsatellite stable increasing the likelihood this variant does not have clinical significance. The p.Gly289 residue is not conserved across mammals and lower species increasing the likelihood that this is a benign variant. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 22, 2020	The MSH6 c.866_867delinsAA (p.Gly289Glu) variant is absent in gnomAD v2.1.1 (PM2_Supporting). An in silico tool developed for MSH6, CoDP, predicts a benign effect of this variant on protein function (BP4; PMID: 23621914), but this prediction has not been confirmed by functional studies. This variant has been reported in a family with Lynch syndrome (PMID: 20028993), and in individuals with endometrial cancer (PMID: 18269114) and breast cancer (PMID: 26898890). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 01, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 15, 2023	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 15, 2022

- -

MSH6-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The MSH6 c.866_867delinsAA variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in several individuals with suspected Lynch syndrome (Devlin et al. 2008. PubMed ID: 18269114; Baglietto et al. 2010. PubMed ID: 20028993; Gordon et al. 2019. PubMed ID: 31422818) and an individual with breast/ovarian cancer (Caminsky et al. 2016. PubMed ID: 26898890). Although this variant is not reported in gnomAD V2.1.1 as c.866_867delinsAA, it is present as two separate variants, c.866G>A and c.867C>A that are found together in 96% and 100% of individuals, respectively, both at a allele frequency of 0.0194% among individuals of European (non-Finnish) descent. The c.866_867delinsAA variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/89572/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Endometrial carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 16, 2023

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 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: rs267608079; hg19: chr2-48025988;