rs576269342

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 2 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 5.73

Variant links:

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]

MSH6 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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 id is 135839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=6, Uncertain_significance=2}. Variant chr2-47801134-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.3151G>A	p.Val1051Ile	missense_variant	4/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.3151G>A	p.Val1051Ile	missense_variant	4/10	1	NM_000179.3	ENSP00000234420	P4	P52701-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000881

AC:

218

AN:

247410

Hom.:

AF XY:

0.00110

AC XY:

148

AN XY:

134332

show subpopulations

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 SAS exome

AF:

0.00703

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.:

Cov.:

AF XY:

0.000545

AC XY:

396

AN XY:

726124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00590

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000125

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000831

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000890

AC:

108

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 5

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	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: 25085752]. -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 2021	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	May 12, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 24, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	This variant is associated with the following publications: (PMID: 23047549, 28873162, 31386297, 31660093) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 19, 2022

- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2020

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.071

.;.;T;T;T;.

Eigen

Benign

-0.091

Eigen_PC

Benign

0.079

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D;T;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.0093

T;T;T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.95

.;.;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.23

.;N;.;N;.;N

REVEL

Uncertain

0.47

Sift

Benign

0.53

.;T;.;T;.;T

Sift4G

Benign

0.69

T;T;T;T;T;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

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.27

gMVP

0.69

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over