2-47799509-T-C

Variant names:

• chr2-47799509-T-C
• rs63751005
• NM_000179.3:c.1526T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_000179.3(MSH6):​c.1526T>C​(p.Val509Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,613,914 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V509L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (6 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:24
• Conservation: PhyloP100: 7.99
• Publications: 25 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 -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.018446863).
• BP6: Variant 2-47799509-T-C is Benign according to our data. Variant chr2-47799509-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 41588.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1526T>C	p.Val509Ala	missense_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.1526T>C	p.Val509Ala	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00107 AC: 269 AN: 251256 AF XY: 0.00107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000552 AC: 807 AN: 1461866 Hom.: 6 Cov.: 34 AF XY: 0.000558 AC XY: 406 AN XY: 727228

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 608 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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: 0.0000800 AC: 89 AN: 1112000

Other (OTH) AF: 0.00179 AC: 108 AN: 60396

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152048 Hom.: 1 Cov.: 32 AF XY: 0.000579 AC XY: 43 AN XY: 74266

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00288 AC: 6 AN: 2086

Alfa AF: 0.000929 Hom.: 3

Bravo AF: 0.000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000708 AC: 86

EpiCase AF: 0.000709

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:6

Aug 09, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6: BS1, BS2 -

Nov 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24055113, 25637381, 15184898, 24978188, 16341805, 22703879, 22949387, 23621914, 20176959, 16237223, 27153395, 25985138, 28531214, 14520694) -

Jul 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2 Benign:4

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 06, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2017

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: This variant has been classified as Likely benign in ClinVar with 3 stars by InSiGHT (expert panel), Pathway Genomics, Emory, CSER_CC_NCGL, and as Benign by Invitae, GeneDx, Ambry, and as VUS by Mayo and Biesecker lab. It has been seen in 9 papers in HGMD, with the comments mostly suggesting that it is likely benign. It is in gnomAD at a frequency of 2.3% of Ashkenazi Jewish chromosomes. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 05, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 24, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 17, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, BS1, BS3 c.1526T>C, located in exon 4 of the MSH6 gene, is predicted to result in the substitution of valine by alanine at codon 509, p.(Val509Ala). The variant allele was found in 263/268090 alleles, with a filter allele frequency of 0.088% at 95% confidence, in the overall gnomAD v2.1.1 database (non-cancer data set), with an increased frequency in the Askenazi Jewish population (BS1). Computational tools predict a deleterious effect of the variant on protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.68) (PP3). This alteration has been reported in the calibrated functional assay CIMRA with functional Odds for Pathogenicity 0.048 (≤ 0.05) (PMID: 31965077) (BS3). To our knowledge, no relevant clinical data nor has been reported for this variant. In addition, the variant was also identified in the following databases: InSiGHT (Class 2: likely not pathogenic), ClinVar (12x benign, 11x likely benign, 4x uncertain significance)and LOVD (1x benign, 4x likely benign, 8x uncertain significance). Based on the currently available information, c.1526T>C is classified as a likely benign variant according to ClinGen-MMR Guidelines Draft v3.1. -

Dec 18, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 5 Uncertain:2 Benign:1

Apr 27, 2017

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. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% in a specific population -

Aug 15, 2016

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 63 year male with a history of over 30 colon polyps and a family history of colon cancer. -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Benign:1

Mar 03, 2022

Fulgent Genetics, Fulgent Genetics

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 p.Val509Ala variant was identified in 4 of 344 proband chromosomes (frequency: 0.01) from individuals or families with hereditary non-polyposis colon cancer and was present in 4 of 1512 control chromosomes (frequency: 0.003) from healthy individuals (Dovrat 2005, Hedge 2005, Peterlongo 2003, Johnston 2012). The variant was also identified in dbSNP (rs63751005) as “with other allele”, ClinVar (classified as likely benign by InSiGHT expert panel in 2013, Color, Eurofins and 4 other submitters; as benign by Invitae, GeneDx, Ambry Genetics and 1 other submitter; and as uncertain significance by Mayo Clinic and 3 other submitters) and UMD-LSDB (observed 5x). The variant was identified in control databases in 278 of 282,624 chromosomes (3 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 244 of 10,364 chromosomes (freq: 0.02), Other in 13 of 7218 chromosomes (freq: 0.002), and European in 21 of 129,016 chromosomes (freq: 0.0002), while it was not observed in the African, Latino, East Asian, Finnish or South Asian populations. The variant had no observed effect on MMR activity in mouse embryonic stem cells (Houlleberghs 2017). The p.Val509 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. -

Breast and/or ovarian cancer Benign:1

Jan 04, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1

Oct 30, 2014

Pathway Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH6-related disorder Benign:1

Apr 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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 04, 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
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;T;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	.;.;M;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	.;D;D;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0030	.;D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.87
MVP		0.96
ClinPred		0.16	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.92
gMVP		0.70
Mutation Taster		=21/79	disease causing

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: rs63751005; hg19: chr2-48026648; COSMIC: COSV52292716;