chr2-47799002-T-C

Position:

chr2-47799002-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP6_Very_Strong

The NM_000179.3(MSH6):c.1019T>C(p.Phe340Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000911 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:5

Conservation

PhyloP100: 5.72

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:

MSH6 (HGNC:):

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

BP6

Variant 2-47799002-T-C is Benign according to our data. Variant chr2-47799002-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 89165.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47799002-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.1019T>C	p.Phe340Ser	missense_variant	4/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.1019T>C	p.Phe340Ser	missense_variant	4/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251320

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000944

AC:

138

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 13, 2022	This missense variant replaces phenylalanine with serine at codon 340 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). An in vitro mismatch repair assay found normal activity (PMID: 31965077). This variant has been reported in an individual affected with colorectal cancer whose tumor showed low microsatellite instability and normal MSH6 immunohistochemistry (PMID: 10699937), and in an individual affected with colorectal cancer with high microsatellite instability and normal MSH6 immunohistochemistry (PMID: 29596542). This variant has also been reported in an individual affected with endometrial cancer and abnormal MSH6 immunohistochemistry (PMID: 32694065). This variant has been identified in 10/282726 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 17, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2022	Variant summary: MSH6 c.1019T>C (p.Phe340Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. A MMR missense classifier tool called PON-MMR prediction method (pathogenic-or-not mismatch repair) classifies this variant as neutral (example, Ali_2012). The variant allele was found at a frequency of 3.6e-05 in 251320 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1019T>C has been reported in the literature in individuals affected with colorectal cancer and/or endometrial cancer (example, Plaschke_2000, Rosa_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Furthermore, a multifactorial probability based assessment reports this variant with a final classification of "Likely not Pathogenic" (IARC class 2) (Thompspon_2013). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in the complete in vitro MMR activity (CIMRA) assay (example, Dorst_2020). Nine 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 (benign/likely benign, n=3; VUS, n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 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: ClinVar: Classified as LB by expert panel in 2013; 2 VUS (GeneDx and Invitae) -

Lynch syndrome 5

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). 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. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 17, 2020	This variant has been assessed to have no effect on mismatch repair activity using an invitro mismatch repair activity assay (PMID: 31965077 (2020)). Several bioinformatic prediction algorithms have classified this variant as a neutral or likely not pathogenic variant (PMID 22290698 (2012), 23621914 (2013), 22949379 (2013)). 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 benign or damaging. Taking into account the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal and other cancers (Plaschke 2000); This variant is associated with the following publications: (PMID: 32926152, 22290698, 10699937, 22949379, 23621914, 11900875, 30212499, 32694065, 31965077) -

Lynch syndrome

Benign:1

Likely benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.052

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.4

.;.;M;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.7

.;N;N;.;N

REVEL

Uncertain

0.54

Sift

Benign

0.049

.;D;D;.;D

Sift4G

Benign

0.81

T;T;T;T;T

Polyphen

0.0080

.;.;B;.;.

Vest4

0.73

MutPred

0.73

.;.;Gain of relative solvent accessibility (P = 0.005);.;.;

MVP

0.94

ClinPred

0.17

GERP RS

3.2

Varity_R

0.12

gMVP

0.39

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