chr2-47803492-C-T

Position:

• chr2-47803492-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The ENST00000234420.11(MSH6):​c.3245C>T​(p.Pro1082Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000183 in 1,614,042 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. P1082S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: MSH6 ENST00000234420.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:11 O:1
• Conservation: PhyloP100: 4.79

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 -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in ENST00000234420.11
• BP4: Computational evidence support a benign effect (MetaRNN=0.11338732).
• BP6: Variant 2-47803492-C-T is Benign according to our data. Variant chr2-47803492-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89358.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=4, Likely_benign=5, not_provided=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000519 (79/152160) while in subpopulation AMR AF= 0.0038 (58/15276). AF 95% confidence interval is 0.00302. There are 2 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3245C>T	p.Pro1082Leu	missense_variant	5/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3245C>T	p.Pro1082Leu	missense_variant	5/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 152042 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000338 AC: 85 AN: 251412 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135874

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000148 AC: 217 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.000147 AC XY: 107 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152160 Hom.: 2 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74376

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00380

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000450

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23621914, 24072394, 24728327, 22290698, 25503501, 27498913, 29368341) -

not specified Benign:3 Other:1

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 06, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2020	Variant summary: MSH6 c.3245C>T (p.Pro1082Leu) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 252712 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database, v2.1 exomes dataset. In addition, the variant was reported in Latino control individuals in the gnomAD database, v3.1 genomes dataset with an even higher frequency (i.e. 0.0038), including 2 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 10 to 30-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism. c.3245C>T has been reported in the literature in individuals affected with (suspected) Lynch syndrome, and breast-, ovarian- or prostate cancer (Zahary_2014, Maxwell_2015, Kalady_2015, Isaaccon Velho_2018, Xiao_2020, Choi_2020). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.45delT (p.Asn16MetfsX7) and BARD1 c.55G>T ( p.Glu19X), both pathogenic variants have been reported in one specimen tested at our laboratory; and MLH1 c.345_349delTACAA (p.Thr116Glufs*4) in Xiao_2020; and BRCA1 c.3020delC (p.Ser1007*) in Choi_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. 4 calling it likely benign, and 4 classifying it as a VUS). Based on the evidence outlined above, the variant was classified as benign. -

Lynch syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 11, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2018	This alteration is classified as likely 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. -

Lynch syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jun 08, 2022

- -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Pro1082Leu variant was identified in 1 of 526 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Kalady 2015). The variant was also identified in dbSNP (ID: rs191109849) as with uncertain significance allele; in the ClinVar and Clinvitae databases as uncertain significance by InSiGHT, Gene Dx, Ambry Genetics, Color Genomics and as likely benign by Invitae. Furthermore, the variant was identified 1X in the Cosmic database and categorized as pathogenic with a FATHMM prediction score of 0.96, with the liver being the primary tissue of origin. The variant was also listed in the Insight Colon Cancer Gene Variant and Insight Hereditary Tumors Databases 2X as class 3. The variant was not identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Zhejiang University, and the Mismatch Repair Genes Variant databases. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles. The variant was identified in control databases in 85 of 277152 chromosomes at a frequency of 0.0003 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: African in 2 of 24032 chromosomes (freq: 0.00008), Other in 5 of 6462 chromosomes (freq: 0.000774), Latino in 52 of 34400 chromosomes (freq: 0.001), European Non-Finnish in 16 of 126676 chromosomes (freq: 0.0001), East Asian in 6 of 18860 chromosomes (freq: 0.0003), European Finnish in 1 of 25790 chromosomes (freq: 0.00004), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, populations. In one study, 616 MMR missense variants for Lynch syndrome patients were downloaded (January 27, 2011) from the International Society for Gastrointestinal Hereditary Tumours (In-SiGHT) database. The purpose was to develop a new consensus predictor to identify variants that are highly likely to be pathogenic, neutral, or of unknown pathogenicity status, this was subsequently applied to the 616 MMR cases and the p.Pro1082Leu variant was assigned a neutral category (Ali 2012). The p.Pro1082 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Lynch syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Ding PR Lab, Sun Yat-sen University Cancer Center

-

- -

MSH6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 09, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;.;T;D;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Benign	1.1	.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.4	.;D;.;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.010	.;D;.;D;D
Sift4G	Benign	0.065	T;D;T;D;T
Polyphen		0.44	.;.;.;B;.
Vest4		0.65
MVP		0.93
ClinPred		0.15	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.34
gMVP		0.76

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: rs191109849; hg19: chr2-48030631; COSMIC: COSV52274543; COSMIC: COSV52274543;