2-47795994-C-G

Variant names:

• chr2-47795994-C-G
• rs587779943
• NM_000179.3:c.558C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000179.3(MSH6):​c.558C>G​(p.Asp186Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D186H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.82
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.086181164).
• BP6: Variant 2-47795994-C-G is Benign according to our data. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600. Variant chr2-47795994-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127600.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.558C>G	p.Asp186Glu	missense_variant	Exon 3 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.558C>G	p.Asp186Glu	missense_variant	Exon 3 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251440 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74152

African (AFR) AF: 0.00 AC: 0 AN: 41320

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Mar 21, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.558C>G (p.Asp186Glu) variant has been reported in the published literature in individuals with breast cancer as well as a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.000008 (2/251440 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -

Mar 24, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MSH6 c.558C>G at the cDNA level, p.Asp186Glu (D186E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asp186Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution and is unlikely to affect protein integrity. MSH6 Asp186Glu occurs at a position that is well conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Asp186Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glutamic acid at codon 186 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251440 chromosomes 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 20, 2022

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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.;T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.086	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;.;.;.
PhyloP100		1.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.57	N;.;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.066	T;.;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.21
MutPred		0.28		Gain of ubiquitination at K187 (P = 0.0506);.;.;.;.;
MVP		0.72
ClinPred		0.12	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.13
Mutation Taster		=91/9	polymorphism

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: rs587779943; hg19: chr2-48023133;