2-47799051-T-C

Variant names:

• chr2-47799051-T-C
• rs749752524
• NM_000179.3:c.1068T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000179.3(MSH6):​c.1068T>C​(p.Gly356Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.213
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-47799051-T-C is Benign according to our data. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47799051-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 183789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.213 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1068T>C	p.Gly356Gly	synonymous_variant	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.1068T>C	p.Gly356Gly	synonymous_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251198 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112010

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Dec 26, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 24, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2018

GeneKor MSA

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31159747) -

Aug 25, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 29, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 5 Benign:1

Dec 23, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Breast and/or ovarian cancer Benign:1

Jun 01, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH6-related disorder Benign:1

Dec 04, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Lynch syndrome Benign:1

Sep 04, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 30, 2025

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
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.3
DANN	Benign	0.79
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs749752524; hg19: chr2-48026190;