2-47800391-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000179.3(MSH6):c.2408A>G(p.Asp803Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,124 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:4

Conservation

PhyloP100: 3.06

Variant links:

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]

MSH6 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18075046).

BP6

Variant 2-47800391-A-G is Benign according to our data. Variant chr2-47800391-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89281.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.2408A>G	p.Asp803Gly	missense_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.2408A>G	p.Asp803Gly	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000838

AC:

AN:

250694

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135486

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000804

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000997

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Feb 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D803G variant (also known as c.2408A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2408. The aspartic acid at codon 803 is replaced by glycine, an amino acid with similar properties. This variant was first reported in a familial CRC kindred and has been shown to reduce the ATP-binding potential of MSH6 (Kolodner RD et al. Cancer Res. 1999 Oct;59:5068-74; Cyr JL and Heinen CD. J. Biol. Chem. 2008 Nov;283:31641-8). This alteration was also identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Jul 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 803 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant protein has reduced nucleotide exchange and ATPase activities (PMID: 18790734). This variant has been reported in individuals affected with colorectal, breast, pancreatic cancer or glioblastoma multiforme (PMID: 10537275, 25186627, 25479140, 26689913, 31391288, 31428572, 33471991), as well as in several healthy controls in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 22/282092 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 11, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 24, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4 c.2408A>G located in exon 4 of the MSH6 gene, is predicted to result in the substitution of aspartic acid by glycine at codon 803; p.(Asp803Gly). This variant is found in 82/1614124 alleles at a frequency of 0,0051% in the gnomAD v4 database, with a filter allele frequency of 0.026% (South Asian dataset) (BS1). Computational tools for this variant suggests no significant impact on splicing (SpliceAI) or protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.007 (BP4). In contrast, a functional study has reported that this variant protein has reduced nucleotide exchange and ATPase activities (PMID: 18790734). The variant has been reported in ClinVar (12x uncertain significance, 2x likely benign, 2x benign), LOVD (2x uncertain significance, 3x not classified) and in the InSiGHT database as Class 3: uncertain (Insufficient evidence). Based on currently available information, and taking into account the apparent discrepancies, the variant c.2408A>G is classified as an uncertain significance variant according to ClinGen-Insight_ACMG_Specifications_MSH6_v1.0.0. -

Lynch syndrome 5

Uncertain:3Benign:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2024

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.2408A>G (p.Asp803Gly) missense change has a maximum founder subpopulation frequency of 0.08% and a maximum non-founder subpopulation frequency of 0.03% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in an individual with colorectal cancer (PMID: 31428572). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Jun 26, 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 trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. -

Jan 27, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Oct 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal and other cancers (PMID: 10537275, 25479140, 26689913, 25186627, 28944238, 31428572); This variant is associated with the following publications: (PMID: 22788692, 22290698, 25637381, 10537275, 23621914, 19766128, 27363283, 26689913, 11900875, 25479140, 25186627, 26206375, 28944238, 31391288, 34445333, 33471991, 24393486, 31428572, 17531815, 21120944, 36922933, 18790734) -

Jan 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.2408A>G (p.Asp803Gly) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 10537275 (1999) and 31428572 (2019)), breast cancer (PMID: 25186627 (2015)), pancreatic cancer (PMID: 25479140 (2015)), and glioblastoma multiforme (PMID: 26689913 (2015)). This variant was also found in individuals with breast cancer well as in reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). A functional study indicated that the variant may uncouple nucleotide processing and DNA binding (PMID: 18790734 (2008)). The frequency of this variant in the general population, 0.00077 (8/10354 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Benign:1

Aug 12, 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: Classified as VUS by expert panel in 2013; no new evidence supporting pathogenicity since then -

Nov 15, 2023

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.2408A>G (p.Asp803Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core 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 5.1e-05 in 1614502 control chromosomes, predominantly at a frequency of 0.00035 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of 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 found primarily in populations of South Asian origin. c.2408A>G has been reported in the literature in cohorts of individuals affected with various cancers such as the Ontario Pancreas cancer study cohort, the TGCA cohort, breast and colorectal cancer (example, Grant_2015, Kolodner_1999, Tung_2015, Lu_2015, Zhunssova_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. A recent study testing MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios to compute a tumor characteristic likelihood ratio (TCLR) included this variant. Predictive performance of TCLR in combination with in silico predictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information resulted in its classification as likely benign (Li_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect affect the ability to be cross linked to ATP, suggesting the mutant appears to uncouple the mismatch binding and ATP hydrolysis activities of the MSH2-MSH6 heterodimer (Cyr_2008). However, the in-vivo implications of this finding are unclear. The following publications have been ascertained in the context of this evaluation (PMID: 10537275, 18790734, 22290698, 23621914, 11900875, 25479140, 25186627, 26689913, 19766128, 31428572, 31391288). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=9) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

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

- -

Lynch syndrome

Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Asp803Gly variant was identified in 4 of 13218 proband chromosomes (frequency: 0.0003) from individuals or families with pancreatic cancer, colorectal or breast cancer, and glioblastoma (Grant 2015, Kolodner 1999, Lu 2015, Tung 2015). The variant was also identified in dbSNP (ID: rs63751450) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight, Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics, and four clinical laboratories), Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (2x as uncertain). The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 23 of 276376 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6458 chromosomes (freq: 0.0002), European in 4 of 125932 chromosomes (freq: 0.00003), Ashkenazi Jewish in 9 of 10136 chromosomes (freq: 0.0009), and South Asian in 9 of 30782 chromosomes (freq: 0.0003), but not in the African, Latino, East Asian, or Finnish populations. The p.Asp803 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, 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. -

Endometrial carcinoma

Uncertain:1

Mar 05, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

.;.;D;T;.

Eigen

Benign

-0.089

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Uncertain

-0.053

MutationAssessor

Benign

1.4

.;.;L;.;.

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

.;N;N;.;D

REVEL

Uncertain

0.58

Sift

Benign

0.19

.;T;T;.;T

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.0030

.;.;B;.;.

Vest4

0.50

MVP

0.94

ClinPred

0.057

GERP RS

5.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.45

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over