2-47799169-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):c.1186C>G(p.Leu396Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 1,614,176 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L396F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (41 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Benign reviewed by expert panel B:28 O:1
• Conservation: PhyloP100: 0.523

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010043681).
• BP6: Variant 2-47799169-C-G is Benign according to our data. Variant chr2-47799169-C-G is described in ClinVar as [Benign]. Clinvar id is 36582.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47799169-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00534 (814/152312) while in subpopulation NFE AF= 0.00772 (525/68028). AF 95% confidence interval is 0.00717. There are 3 homozygotes in gnomad4. There are 406 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.1186C>G	p.Leu396Val	missense_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.1186C>G	p.Leu396Val	missense_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00540 AC: 1355 AN: 251120 Hom.: 7 AF XY: 0.00530 AC XY: 719 AN XY: 135750

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.00714

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00681 AC: 9952 AN: 1461864 Hom.: 41 Cov.: 34 AF XY: 0.00659 AC XY: 4793 AN XY: 727240

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.00765

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.00534 AC: 814 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74480

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.00772

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00668 Hom.: 2

Bravo AF: 0.00386

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00518 AC: 629

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00593

ClinVar

Significance: Benign

Submissions summary: Benign:28 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 23, 2018	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 15, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Lynch syndrome 5 Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Oct 06, 2023	BA1 based on allele frequency in NFE of 0.007213. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 20, 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 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -

Lynch syndrome Benign:3

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Multifactorial likelihood analysis posterior probability <0.001 -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2015	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 06, 2021

- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Leu396Val variant has been previously reported in about 9/5154 proband chromosomes in individuals with Lynch syndrome, sporadic colorectal cancer and endometrial cancer. It has also been observed in 3/5148 control chromosomes (Kim_2004_15340264, Kolodner_1999_10537275, Martinez_2010_20176959, Niessen_2006_16408224, Nilbert_2009_18566915, Perez-Cabornero_2009_19250818, Schafmayer_2007_17417778, Steinke_2008_18301448, Vahteristo_2005_15805151). It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs2020908) with an average heterozygosity score and standard error of 0.008+/-0.064, and a global minor allele frequency (MAF) of 0.004 (1000 Genomes), increasing the likelihood that this is a benign variant. The variant was also identified as a low frequency variant from HapMap samples of different populations of origin as well as in the EPS project as a low frequency variant increasing the liklihood this variant is benign. This residue is conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest this variant may impact protein function. However, this information is not very predictive of pathogenicity. Two functional Saccharomyces cerevisiae-based studies have shown that the MMR activity of the variant is comparable to the wild type protein (Kolodner_1999_10537275, Martinez_2010_20176959), increasing the likelihood that the p.Leu396Val variant is not clinically significant. In summary, based on the above information, this variant is classified as Benign. -

Lynch syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

MSH6: BP4, BS2 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Benign	0.97
Eigen	Benign	-0.019
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.53	.;.;P;.;.
Vest4		0.35
MVP		0.91
ClinPred		0.024	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs2020908; hg19: chr2-48026308; COSMIC: COSV52290559; COSMIC: COSV52290559;