rs576269342

Variant names:

• chr2-47801134-G-A
• rs576269342
• NM_000179.3:c.3151G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47801134-G-A
• chr2-47801134-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000179.3(MSH6):​c.3151G>A​(p.Val1051Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000346 in 1,611,768 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1051L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 5.73
• Publications: 9 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 -11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 51 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.009309322).
• BP6: Variant 2-47801134-G-A is Benign according to our data. Variant chr2-47801134-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135839.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000125 (19/152324) while in subpopulation SAS AF = 0.00394 (19/4820). AF 95% confidence interval is 0.00258. There are 1 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.3151G>A	p.Val1051Ile	missense	Exon 4 of 10	NP_000170.1
	MSH6	NM_001406795.1		c.3247G>A	p.Val1083Ile	missense	Exon 5 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.3157G>A	p.Val1053Ile	missense	Exon 4 of 10	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.3151G>A	p.Val1051Ile	missense	Exon 4 of 10	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*2498G>A		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1
	MSH6	ENST00000445503.5	TSL:1	n.*2498G>A		3_prime_UTR	Exon 3 of 9	ENSP00000405294.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000881 AC: 218 AN: 247410 AF XY: 0.00110

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: 0.00

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000369 AC: 538 AN: 1459444 Hom.: 2 Cov.: 34 AF XY: 0.000545 AC XY: 396 AN XY: 726124

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00590 AC: 509 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51058

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111978

Other (OTH) AF: 0.000232 AC: 14 AN: 60384

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000517 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000890 AC: 108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4

Oct 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 24, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Jun 03, 2021

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.

Jan 27, 2025

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000179.3(MSH6):c.3151G>A (p.Val1051Ile) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is observed in one or more well-documented healthy adults. There is a small physicochemical difference between valine and isoleucine, which is not likely to impact secondary protein structure as these residues share similar properties. The nucleotide c.3151 in MSH6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Benign.

Lynch syndrome 5 Uncertain:1 Benign:2

Jan 03, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].

Dec 11, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Apr 29, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 4/5 in silico programs predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 107/119266 (1/1114), predominantly in the South Asian cohort, 106/16430 (1/154), which exceeds the predicted maximum expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, suggesting that the variant of interest is a common polymorphism found in population(s) of South Asian origin. The variant of interest was observed in affected individuals via a publication, although with limited information (ie lack of co-occurrence/co-segregation data). Multiple reputable clinical laboratories cite the variant with a classification of "uncertain significance," however, it should be noted that these classifications were evaluated previous to ExAC data being available. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.

Apr 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23047549, 28873162, 31386297, 31660093)

Hereditary breast ovarian cancer syndrome Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast and/or ovarian cancer Benign:1

Jul 19, 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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Val1051Ile variant was identified in 2 of 3786 proband chromosomes (frequency: 0.0005) from individuals or families with epithelial ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs576269342) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx; and as uncertain significance by three submitters), and Cosmic database (2x in upper aerodigestive tract tissue). The variant was not identified in COGR, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 218 of 247410 chromosomes (1 homozygous) at a frequency of 0.0009 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: South Asian in 215 of 30590 chromosomes (freq: 0.007) and Other in 3 of 6076 chromosomes (freq: 0.0005); it was not observed in the Ashkenazi Jewish, African, East Asian, Finnish, European, or Latino populations. The p.Val1051 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

MSH6-related disorder Benign:1

Jul 29, 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).

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.091
Eigen_PC	Benign	0.079
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.95	L
PhyloP100		5.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.47
Sift	Benign	0.53	T
Sift4G	Benign	0.69	T
Polyphen		0.040	B
Vest4		0.22
MutPred		0.70		Gain of catalytic residue at V1051 (P = 0.187)
MVP		0.83
ClinPred		0.054	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.27
gMVP		0.69
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs576269342; hg19: chr2-48028273; COSMIC: COSV52273761; COSMIC: COSV52273761;