rs545466048

chr2-47806769-T-Achr2-47806769-T-Cchr2-47806769-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000179.3(MSH6):c.4002-10T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,542,738 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).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: MSH6 NM_000179.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.009428
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:12
• Conservation: PhyloP100: -2.24

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-47806769-T-A is Benign according to our data. Variant chr2-47806769-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89507.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=6, Benign=3}. Variant chr2-47806769-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000295 (42/142178) while in subpopulation EAS AF= 0.00222 (11/4962). AF 95% confidence interval is 0.00124. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.4002-10T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-10T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 42 AN: 142084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000620

Gnomad ASJ AF: 0.00122

Gnomad EAS AF: 0.00221

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000233

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000276 AC: 60 AN: 217244 Hom.: 0 AF XY: 0.000328 AC XY: 39 AN XY: 118808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000194

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.000448

Gnomad SAS exome AF: 0.000149

Gnomad FIN exome AF: 0.000356

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000379

GnomAD4 exome AF: 0.000365 AC: 511 AN: 1400560 Hom.: 2 Cov.: 31 AF XY: 0.000374 AC XY: 261 AN XY: 697862

Gnomad4 AFR exome AF: 0.0000976

Gnomad4 AMR exome AF: 0.000220

Gnomad4 ASJ exome AF: 0.00158

Gnomad4 EAS exome AF: 0.00609

Gnomad4 SAS exome AF: 0.000184

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.000295 AC: 42 AN: 142178 Hom.: 0 Cov.: 31 AF XY: 0.000274 AC XY: 19 AN XY: 69290

Gnomad4 AFR AF: 0.0000788

Gnomad4 AMR AF: 0.000619

Gnomad4 ASJ AF: 0.00122

Gnomad4 EAS AF: 0.00222

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000233

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000293 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2019	This variant is associated with the following publications: (PMID: 30306255, 25561518, 26181448, 21056691) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 11, 2019	- -

not specified Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 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: 1 paper in HGMD describes as VUS; ClinVar: 1LB; Unlikely to impact splicing -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2019	Variant summary: MSH6 c.4002-10T>A alters a non-conserved nucleotide. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00026 in 244976 control chromosomes (gnomAD). The observed variant frequency is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. The variant, c.4002-10T>A, has been reported in the literature in colorectal, gastric or breast cancer patients without strong evidence for causality (Limburg_2011, Yamashita_2013, Bonache_2018). A co-occurrence with another pathogenic variant has been reported (MSH6 c.3477C>G, p.Tyr1159X; internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS (n=5), Likely benign (n=1), Benign (n=1)) and one expert panel, InSiGHT, classified as uncertain significance before 2014. Based on the evidence outlined above, the variant was classified as benign. -

Lynch syndrome 5 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 18, 2019	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2016	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. -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

May 21, 2021

ACMG categories: PM2,PP3 -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6, c.4002-10T>A, r.(spl?) variant was identified in 31 of 48 proband chromosomes (frequency: 0.6) from individuals or families with familial colorectal cancer (Lucci-Cordisco 2001). The variant was also identified in dbSNP (ID: rs545466048) as “With Uncertain significance allele”, ClinVar (1x likely benign: Invitae; 3x uncertain significance: InSiGHT, GeneDx, Partners HealthCare), COSMIC (1x confirmed somatic in Wilms tumour of kidney), UMD-LSDB (biological significance neutral; variation in splice site consensus value <10%), Insight Colon Cancer Gene Variant Database (3x uncertain significance), Mismatch Repair Genes Variant Database (as c.4002-8dupA polymorphism in Verma 1999 and Lucci-Cordisco 2001, describing this as a poly A expansion where “sequencing suggests that different length variants exist or are highly prone to stuttering so that it is not possible to sequence across them"), Insight Hereditary Tumors Database (3x effect unknown), databases. The variant was not identified in MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 57 of 213460 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

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

Mar 23, 2022

- -

MSH6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.0
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0094
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.090		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: rs545466048; hg19: chr2-48033908; COSMIC: COSV52275389; COSMIC: COSV52275389;