rs372916347

Variant names:

• chr2-47799957-G-A
• rs372916347
• NM_000179.3:c.1974G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47799957-G-A
• chr2-47799957-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000179.3(MSH6):​c.1974G>A​(p.Val658Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,614,018 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.499
• Publications: 3 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-47799957-G-A is Benign according to our data. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629. Variant chr2-47799957-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 182629.
• BP7: Synonymous conserved (PhyloP=-0.499 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1974G>A	p.Val658Val	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.1974G>A	p.Val658Val	synonymous_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000279 AC: 7 AN: 251140 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.0000688 AC XY: 50 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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: 0.0000944 AC: 105 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

African (AFR) AF: 0.0000725 AC: 3 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

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

Alfa AF: 0.0000665 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Jan 25, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 08, 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. -

Lynch syndrome Uncertain:1 Benign:1

Dec 28, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Apr 24, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MSH6 c.1974G>A at the DNA level. Although the variant is silent at the coding level, preserving a Valine at codon 658, multiple splicing models predict the creation of a novel cryptic splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 c.1974G>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 1974, is conserved in mammals. Based on currently available evidence, it is unclear whether MSH6 c.1974G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

not specified Benign:1

Jun 13, 2022

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 30, 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 15, 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	-0.57
CADD	Benign	2.0
DANN	Benign	0.80
PhyloP100		-0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372916347; hg19: chr2-48027096;