NM_000179.3:c.4002-10T>A

Variant names:

• chr2-47806769-T-A
• rs545466048
• NM_000179.3:c.4002-10T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000179.3(MSH6):​c.4002-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,542,738 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Scores: Splicing: ADA: 0.009428
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:13
• Conservation: PhyloP100: -2.24
• Publications: 7 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=-0.82).
• BP6: Variant 2-47806769-T-A is Benign according to our data. Variant chr2-47806769-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89507.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000295 (42/142178) while in subpopulation EAS AF = 0.00222 (11/4962). AF 95% confidence interval is 0.00124. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-10T>A		intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1
FBXO11	NM_001190274.2	c.*1349A>T		downstream_gene_variant		ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-10T>A		intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5
FBXO11	ENST00000403359.8	c.*1349A>T		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 42 AN: 142084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000620

Gnomad ASJ AF: 0.00122

Gnomad EAS AF: 0.00221

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000233

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000276 AC: 60 AN: 217244 AF XY: 0.000328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000194

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.000448

Gnomad FIN exome AF: 0.000356

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000379

GnomAD4 exome AF: 0.000365 AC: 511 AN: 1400560 Hom.: 2 Cov.: 31 AF XY: 0.000374 AC XY: 261 AN XY: 697862

African (AFR) AF: 0.0000976 AC: 3 AN: 30740

American (AMR) AF: 0.000220 AC: 9 AN: 40944

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 40 AN: 25316

East Asian (EAS) AF: 0.00609 AC: 233 AN: 38248

South Asian (SAS) AF: 0.000184 AC: 15 AN: 81560

European-Finnish (FIN) AF: 0.000123 AC: 6 AN: 48902

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5544

European-Non Finnish (NFE) AF: 0.000178 AC: 191 AN: 1071276

Other (OTH) AF: 0.000224 AC: 13 AN: 58030

GnomAD4 genome AF: 0.000295 AC: 42 AN: 142178 Hom.: 0 Cov.: 31 AF XY: 0.000274 AC XY: 19 AN XY: 69290

African (AFR) AF: 0.0000788 AC: 3 AN: 38058

American (AMR) AF: 0.000619 AC: 9 AN: 14528

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 4 AN: 3284

East Asian (EAS) AF: 0.00222 AC: 11 AN: 4962

South Asian (SAS) AF: 0.00 AC: 0 AN: 4578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000233 AC: 15 AN: 64430

Other (OTH) AF: 0.00 AC: 0 AN: 1962

Alfa AF: 0.000293 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30306255, 25561518, 26181448, 21056691) -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:3 Benign:1

Jun 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD describes as VUS; ClinVar: 1LB; Unlikely to impact splicing -

May 30, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.4002-10T>A alters a non-conserved nucleotide. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00026 in 244976 control chromosomes (gnomAD). The observed variant frequency is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. The variant, c.4002-10T>A, has been reported in the literature in colorectal, gastric or breast cancer patients without strong evidence for causality (Limburg_2011, Yamashita_2013, Bonache_2018). A co-occurrence with another pathogenic variant has been reported (MSH6 c.3477C>G, p.Tyr1159X; internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS (n=5), Likely benign (n=1), Benign (n=1)) and one expert panel, InSiGHT, classified as uncertain significance before 2014. Based on the evidence outlined above, the variant was classified as benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Oct 09, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP5 MSH6 c.4002-10T>A is an intronic variant located close to a canonical splice site. This variant is found in 7/16524 with a filter allele frequency of 0.022 at 95% confidence in the gnomAD v2.1.1 database (East Asian non-cancer data set)(BS1). Computational tools on splicing for this variant are inconclusive (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.34). It has been reported in at least 2 colorectal cancer samples with maintained MSH6 expression (PMID:23523604 and internal data)(BP5). In addition, this variant has been reported in ClinVar (3x benign, 9x likely benign, 6x uncertain significance), (4x likely benign, 4x uncertain significance) and in the InSiGHT (as Class3: uncertain: ‘insuficient evidence’) databases. Based on currently available information, the variant c.4002-10T>A is classified as a likely benign variant according to ACMG guidelines. -

Dec 28, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2016

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 5 Uncertain:1 Benign:1

Apr 18, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Uncertain:1

May 21, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM2,PP3 -

Breast and/or ovarian cancer Benign:1

Mar 23, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6, c.4002-10T>A, r.(spl?) variant was identified in 31 of 48 proband chromosomes (frequency: 0.6) from individuals or families with familial colorectal cancer (Lucci-Cordisco 2001). The variant was also identified in dbSNP (ID: rs545466048) as “With Uncertain significance allele”, ClinVar (1x likely benign: Invitae; 3x uncertain significance: InSiGHT, GeneDx, Partners HealthCare), COSMIC (1x confirmed somatic in Wilms tumour of kidney), UMD-LSDB (biological significance neutral; variation in splice site consensus value <10%), Insight Colon Cancer Gene Variant Database (3x uncertain significance), Mismatch Repair Genes Variant Database (as c.4002-8dupA polymorphism in Verma 1999 and Lucci-Cordisco 2001, describing this as a poly A expansion where “sequencing suggests that different length variants exist or are highly prone to stuttering so that it is not possible to sequence across them"), Insight Hereditary Tumors Database (3x effect unknown), databases. The variant was not identified in MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 57 of 213460 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

MSH6-related disorder Benign:1

Jan 27, 2023

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). -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.82
CADD	Benign	3.0
DANN	Benign	0.81
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0094
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.090		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: rs545466048; hg19: chr2-48033908; COSMIC: COSV52275389; COSMIC: COSV52275389;