chr2-47800616-T-C

Position:

• chr2-47800616-T-C

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.2633T>C​(p.Val878Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,614,190 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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. V878G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (40 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:33 O:1
• Conservation: PhyloP100: 0.373

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.035881698).
• BP6: Variant 2-47800616-T-C is Benign according to our data. Variant chr2-47800616-T-C is described in ClinVar as [Benign]. Clinvar id is 8931.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47800616-T-C is described in Lovd as [Benign]. Variant chr2-47800616-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00462 (704/152330) while in subpopulation AMR AF= 0.00732 (112/15300). AF 95% confidence interval is 0.00662. There are 5 homozygotes in gnomad4. There are 348 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.2633T>C	p.Val878Ala	missense_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.2633T>C	p.Val878Ala	missense_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 708 AN: 152212 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00511 AC: 1280 AN: 250386 Hom.: 9 AF XY: 0.00559 AC XY: 757 AN XY: 135488

Gnomad AFR exome AF: 0.000879

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00631

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00707

Gnomad OTH exome AF: 0.00656

GnomAD4 exome AF: 0.00586 AC: 8568 AN: 1461860 Hom.: 40 Cov.: 34 AF XY: 0.00607 AC XY: 4411 AN XY: 727234

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00999

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00650

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00640

Gnomad4 OTH exome AF: 0.00517

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152330 Hom.: 5 Cov.: 32 AF XY: 0.00467 AC XY: 348 AN XY: 74494

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00714

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00629 Hom.: 6

Bravo AF: 0.00446

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00524 AC: 636

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:33 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:11 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2016	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Valine (V) with a small size and hydrophobic Alanine (A). 2/3 in silico tools predict the variant to be neutral (SNPs&GO and mutation taster were not considered due to low reliability index). The variant was observed in the large and broad cohorts of the ExAC project across diverse ethnicities at an allele frequency of 0.52% which exceeds ~ 36 times the maximal expected allele frequency of a disease causing MSH6 allele (0.0142%). Additionally, 4 homozygous occurrences are also reported in ExAC indicating neutrality. The variant was reported in several patients, however without strong evidence for pathogenicity. Independent functional studies concluded the variant to slightly impair MSH6 MMR functions however a large case control study failed to show association between CRC and the variant (Lipkin_NG_2004). Several clinical diagnostic centers and databases classify variant as Benign (without evidence to independently evaluate). Moreover, UMD lists two co-occurrences with the following pathogenic MSH6 variants: c.3268_3274del (p.Glu1090LysfsX23) and c.3514dup (p.Arg1172LysfsX5). Considering all evidence, the variant was classified as Benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Lynch syndrome 5 Uncertain:2 Benign:6

Uncertain significance, no assertion criteria provided	literature only	OMIM	Oct 01, 2001	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
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	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 18, 2023	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2015	- -
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	curation	Sema4, Sema4	Sep 29, 2020	- -

not provided Benign:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MSH6: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 27, 2021

- -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The Val878Ala variant has been previously identified in the literature and by our laboratory. More than 39 probands have been cited in the literature including individuals with endometrial cancer, MSI, microsatellite Mutator phenotype (MMP), and individual meeting Amsterdam Criteria for Lynch syndrome (Charames 2000, Barnetson 2008, Jennifer 2008, Wasielewski 2010, Plaschke 2006, Korhonen 2008, Hampel 2006, Ohmiya 2001, Ohmiya 2001, Berends 2002, Peterlongo 2003, Lipkin 2004, Dovrat 2005). However, there was conflicting information as to the relationship of this variant with disease status. This variant was identified in combination with another variant on the other allele in two different individual, one of whom had a nonsense variant (Plaschke 2006, Ohmiya 2001) raising the possibility that this is a benign variant. Furthermore, over 51 control individuals have been identified with this variant in the literature. In one large case control study, 25/2384 cases had this variant and 46/2630 race matched controls (From Northern Israel and Haifa) were carriers of this variant (Lipkin 2004). The variant has also been observed in other populations at lower frequency (dbSNP:rs2020912). This variant is conserved in mammals and other vertebrates but not in fruitfly. In-silico analysis (Sift, AlignGVGD, MAPP) provide conflicting data, and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with absolute certainty but we would lean towards a more likely benign role for this variant. -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability <0.001 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Colorectal / endometrial cancer Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.0
DANN	Benign	0.73
DEOGEN2	Benign	0.41	.;.;T;T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.75	.;T;T;T;T
MetaRNN	Benign	0.036	T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.1	.;.;L;.;.
MutationTaster	Benign	0.000026	A;A;A;A
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	.;N;N;.;N
REVEL	Benign	0.15
Sift	Benign	0.34	.;T;T;.;T
Sift4G	Benign	0.48	T;T;T;T;T
Polyphen		0.036	.;.;B;.;.
Vest4		0.17
MVP		0.85
ClinPred		0.0017	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.45

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: rs2020912; hg19: chr2-48027755; COSMIC: COSV52276766; COSMIC: COSV52276766;