2-47790942-A-G

Position:

• chr2-47790942-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000179.3(MSH6):​c.276A>G​(p.Pro92Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,796 control chromosomes in the GnomAD database, including 24,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1786 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22908 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:21
• Conservation: PhyloP100: 0.115

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-47790942-A-G is Benign according to our data. Variant chr2-47790942-A-G is described in ClinVar as [Benign]. Clinvar id is 36587.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47790942-A-G is described in Lovd as [Benign]. Variant chr2-47790942-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.115 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.276A>G	p.Pro92Pro	synonymous_variant	2/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.276A>G	p.Pro92Pro	synonymous_variant	2/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21823 AN: 152176 Hom.: 1787 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0591

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.135 AC: 33880 AN: 251472 Hom.: 2824 AF XY: 0.137 AC XY: 18673 AN XY: 135916

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0850

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0737

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.170 AC: 249074 AN: 1461502 Hom.: 22908 Cov.: 34 AF XY: 0.168 AC XY: 122076 AN XY: 727102

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0907

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0744

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.143 AC: 21824 AN: 152294 Hom.: 1786 Cov.: 32 AF XY: 0.139 AC XY: 10325 AN XY: 74458

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0590

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.161

Alfa AF: 0.160 Hom.: 1610

Bravo AF: 0.146

Asia WGS AF: 0.0450 AC: 160 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.209

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 22, 2011	This variant is classified as benign because it does not result in an amino acid change and is common in the general population (rs1800932, MAF >1%). -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	#N/A -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. Only high quality variants are reported. -

Lynch syndrome 5 Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Lynch syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2015	- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.5
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800932; hg19: chr2-48018081; COSMIC: COSV52275820;