2-47800381-G-C

Variant names:

• chr2-47800381-G-C
• rs61748083
• NM_000179.3:c.2398G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BP6_Very_Strong

The NM_000179.3(MSH6):​c.2398G>C​(p.Val800Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V800I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:12 B:11
• Conservation: PhyloP100: 5.78
• Publications: 14 publications found

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]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 43 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.20331198).
• BP6: Variant 2-47800381-G-C is Benign according to our data. Variant chr2-47800381-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 89279.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.2398G>C	p.Val800Leu	missense_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.2398G>C	p.Val800Leu	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152064 Hom.: 0 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000917 AC: 23 AN: 250774 AF XY: 0.000118

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1461858 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 88 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000153 AC: 170 AN: 1112006

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000683 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:12 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:2 Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 3 papers, all describe as VUS/non-pathogenic; ExAC: 2/11540 Latino chromosomes -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.2398G>C (p.Val800Leu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250774 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). c.2398G>C has been reported in the literature in individuals affected with ovarian cancer (Pal_2012), renal cell carcinoma (Lu_2015), Breast Cancer (Wang_2018) and colorectal cancer (Kim_2004, Kolodner_1999, Shirts_2015), and in one report with positive segregation data, although the number of affected individuals in the family was not reported (Liccardo_2017). Some reports classified the variant as uncertain significance (example: Murphy_2022 and Tsaousis_2019). Co-occurrence with other pathogenic variant(s) have been reported (BRCA1 c.1252G>T, p.Glu418Ter), providing supporting evidence for a benign role for the variant (Wang_2018). At least one publication reports experimental evidence evaluating an impact on protein function. This variant had 91.8% activity in an in vitro MMR activity (CIMRA) assay supporting a benign role for this variant (Drost_2020). The following publications have been ascertained in the context of this evaluation (PMID: 10537275, 15340264, 22290698, 23047549, 23621914, 26689913, 26845104, 28481244, 30982232, 31159747, 31965077, 35128723). ClinVar contains an entry for this variant (Variation ID: 89279). Based on the evidence outlined above, the variant was classified as likely benign. -

May 07, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.2398G>C; p.Val800Leu variant (rs61748083) is reported in the literature in individuals with colorectal cancer or ovarian cancer (Kim 2004, Kolodner 1999, Pal 2012, Shirts 2016), but is also reported in a healthy control (Kolodner 1999). This variant is reported in ClinVar (Variation ID: 89279). It is found in the general population with an overall allele frequency of 0.009% (26/282172 alleles) in the Genome Aggregation Database. The valine at codon 800 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Kim JC et al. Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer. 2004;3(2):129-37. Kolodner RD et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999 Oct 15;59(20):5068-74. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 16, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Uncertain:2 Benign:1

Oct 19, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.2398G>C (p.Val800Leu) missense change has a maximum subpopulation frequency of 0.017% in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48027520-G-C). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 26845104, 28481244, 10537275). In case control studies, this variant was identified in one control participant and no colorectal cancer patients (PMID: 30267214), while in another case control study the variant was identified at a similar frequency in colorectal cancer cases and normal controls (PMID: 10537275). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. -

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 20, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 5 Uncertain:1 Benign:2

Dec 31, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Breast and/or ovarian cancer Uncertain:1

Apr 20, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

MSH6-related disorder Uncertain:1

May 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 c.2398G>C variant is predicted to result in the amino acid substitution p.Val800Leu. This variant has been reported in individuals with a history of ovarian and colorectal cancer (Kolodner et al. 1999. PubMed ID: 10537275; Supplementary Table 1, Pal et al. 2012. PubMed ID: 23047549; Table S1, Shirts et al. 2016. PubMed ID: 26845104), but was also identified in unaffected control cohorts (Kolodner et al. 1999. PubMed ID: 10537275; Supplementary Table 1, Amendola et al. 2015. PubMed ID: 25637381). This variant was reported in a family with colorectal cancer who had negative testing in MLH1 and MSH2, and also reported to segregate with Lynch syndrome phenotypes, although segregation details were not provided (Table 1, Liccardo et al. 2017. PubMed ID: 28481244). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. MSH6-specific algorithms predict that this variant is neutral (http://structure.bmc.lu.se/PON-MMR2/; Ali et al. 2012. PubMed ID: 22290698). This variant has conflicting evidence in ClinVar including interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/89279/?new_evidence=false). Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Val800Leu variant was identified in 1 of 558 proband chromosomes (frequency 0.002) from individuals with colorectal cancer (Kim 2004, Kolodner 1999) and was identified in 1 of 1038 control chromosomes (frequency 0.001) from these studies, increasing the likelihood that this may be a low frequency polymorphism. This variant was also identified in dbSNP (ID# rs61748083) “with untested allele”, in the Exome Variant Server ESP Project with a frequency of 0.0002 in European American alleles, and in the HGMD, MutDB, MMR DB, and InSIGHT Colon Cancer databases. The p.Val800 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. In addition, two in silico studies which assessed the impact of the variant on protein structure and function predicted this variant was neutral (Ali 2012, Terui 2013). However, this information is not predictive enough to rule out pathogenicity. 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 predicted benign. -

Lynch syndrome 1 Benign:1

Jun 13, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

Multifactorial likelihood analysis posterior probability < 0.05 (0.028) -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.34	.;.;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.070
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.34	.;.;N;.;.
PhyloP100		5.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.74	.;N;N;.;N
REVEL	Uncertain	0.49
Sift	Benign	0.29	.;T;T;.;T
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.0080	.;.;B;.;.
Vest4		0.15
MVP		0.93
ClinPred		0.027	T
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.30
gMVP		0.26
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs61748083; hg19: chr2-48027520; COSMIC: COSV99317336; COSMIC: COSV99317336;