2-47804959-A-T

Position:

• chr2-47804959-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):​c.3488A>T​(p.Glu1163Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,614,156 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:16 O:1
• Conservation: PhyloP100: 8.92

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013140768).
• BP6: Variant 2-47804959-A-T is Benign according to our data. Variant chr2-47804959-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 89400.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47804959-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000506 (77/152306) while in subpopulation EAS AF= 0.0123 (64/5188). AF 95% confidence interval is 0.00991. There are 1 homozygotes in gnomad4. There are 41 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	c.3488A>T	p.Glu1163Val	missense_variant	6/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3488A>T	p.Glu1163Val	missense_variant	6/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152188 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: 0.0125

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00104 AC: 262 AN: 251392 Hom.: 1 AF XY: 0.000972 AC XY: 132 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0121

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000385 AC: 563 AN: 1461850 Hom.: 2 Cov.: 31 AF XY: 0.000404 AC XY: 294 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000480 Hom.: 0

Bravo AF: 0.000684

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: ClinVar: Lik Ben by expert panel -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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	Jan 02, 2022	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 07, 2020	- -

Lynch syndrome 5 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 09, 2018	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2016	Variant summary: The MSH6 c.3488A>T (p.Glu1163Val) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome. This variant was found in 148/121590 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0137604 (119/8648). This frequency is about 97 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. It was also reported in HNPCC patients, however without strong evidence for pathogenicity such as co-segregation of the variant with the disease in affected family members. Additionally, databases and multiple clinical diagnostic laboratories classify variant as Benign/Likely benign. Considering the high prevalence of the variant in the East Asian population, it was classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MSH6: BS1 -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 29, 2021

- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Glu1163Val variant was identified in 4 of 2866 proband chromosomes (frequency: 0.001) from individuals or families with HNPCC and colorectal cancer), and was present in 5 of 642 control chromosomes (frequency: 0.008) from healthy individuals (Ali 2012, Limburg 2011, Nilbert 2009, Shin 2004, Yan 2007). The variant was also identified in dbSNP (ID: rs63750252 “With untested allele”, with a minor allele frequency of 0.0028 (14 of 5000 chromosomes in 1000 Genomes Project). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 143 of 121316 alleles (frequency: 0.001179) (including 119 of 8648:freq 0.01376 of East Asian chromosomes) and was not found in African and European (Finnish) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Glu1163Val variant was identified in the Clinvar database and was classified as Benign by GeneDx, Ambry Genetics and Invitae; as Likely Benign by InSIGHT; as a variant of uncertain significance by Mayo Clinic Genetic Testing Laboratory and no classification was provided by ITMI. In UMD Colon Genes database the variant was identified 2X and classified as unknown. The variant co-occurred with a pathogenic MSH2 variant (c.518T>C, p.Leu173Pro). The InSIGHT database identified the variant 7X and classified it as likely not pathogenic and in the Zheijiang database the variant was identified 1X and classified unknown. In COSMIC database the variant was identified in a lymphoid tumour and in a culture. The p.Glu1163 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Valine variant may impact the protein, however this information is not predictive enough to assume pathogenicity. Additionally, in a Chinese population study the c.3488A>T was also found in the controls; the rate was approximately 3.65% (5/137) (Yan 2007). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Lynch syndrome Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% in specific population -

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
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;.;T;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.0	.;D;.;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.022	.;D;.;D;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.57	.;.;.;P;.
Vest4		0.86
MVP		0.92
ClinPred		0.14	T
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.68
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750252; hg19: chr2-48032098; COSMIC: COSV52275797; COSMIC: COSV52275797;