2-47791001-A-G

Position:

chr2-47791001-A-G

Variant summary

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

The NM_000179.3(MSH6):c.335A>G(p.Asn112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2

Conservation

PhyloP100: 6.62

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=0.21720853).

BP6

Variant 2-47791001-A-G is Benign according to our data. Variant chr2-47791001-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127586.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 link	c.335A>G	p.Asn112Ser	missense_variant	2/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 link	c.335A>G	p.Asn112Ser	missense_variant	2/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152216

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251490

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

163

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 10, 2023	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	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 15, 2023	This missense variant replaces asparagine with serine at codon 112 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with mismatch DNA repair proficient endometrial cancer (PMID: 31307542) and several individuals affected with breast cancer (PMID: 29684080, 33471991; Lovejoy, et al. 2018). This variant has been identified in 7/282896 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 29, 2021	- -

Lynch syndrome 5

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.335A>G (p.Asn112Ser) in MSH6 gene has been reported previously in individuals affected with Lynch syndrome (Singh et al. 2020; Lasota et al. 2020). The p.Asn112Ser variant is present with an allele frequency of 0.002% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Benign / Likely Benign / Uncertain Significance (multiple submissions). Computational evidence (SIFT - tolerated; Polyphen - benign; MutationTaster - disease causing) predicts conflicting effect on protein structure and function for this variant. The amino acid change p.Asn112Ser in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 112 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Feb 15, 2023	The MSH6 c.335A>G (p.Asn112Ser) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. This variant has been reported in an individual with endometrial cancer who has a MSS tumor and did not meet Amsterdam criteria (PMID: 31307542). It has also been reported in an individual with a personal history of endometrial cancer, skin cancer, and no reported family history of cancer (PMID: 32634176). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2024	Variant summary: MSH6 c.335A>G (p.Asn112Ser) results in a conservative amino acid change located in the PWWP domain 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 2.5e-05 in 277252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.335A>G has also been reported in the literature in individuals affected with Breast Cancer, Biliary tract cancer and Skin cancer, without strong evidence for causality (Hu_GM_2022, Okawa_JH_2023, Singh_PLoSO_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The variant has been reported in the literature as a germline variant in two breast invasive carcinoma samples from The Cancer Genome Atlas; in one sample co-occurring with a germline pathogenic variant (ATM c.5932G>T, p.Glu1978X) (Yehia_2018), additional co-occurrences with other pathogenic variants have also been reported (MLH1 c.116+2T>C, UMD database; MLH1 c.1489dupC, p.Arg497ProfsX6, LabCorp internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36169650, 35449176, 36243179, 32634176, 29684080). ClinVar contains an entry for this variant (Variation ID: 127586). 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	Jan 25, 2017	The p.Asn112Ser variant in MSH6 has not been previously reported in individuals with Lynch syndrome. This variant has been identified in 1/10406 of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs587779934). Computational prediction tools and conservation analysis suggest that the p.Asn112Ser variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the p.Asn112Ser variant is uncertain. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with endometrial, breast, or ovarian cancer, but also in unaffected controls (PMID: 29684080, 31307542, 32634176, 33471991, 36169650, 35449176); This variant is associated with the following publications: (PMID: 28292439, 23729658, 33471991, 32634176, 35449176, 36169650, 29684080, 36243179, 31422818, 31307542) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 07, 2024	The MSH6 c.335A>G (p.Asn112Ser) variant has been reported in the published literature in individuals with endometrial cancer (PMID: 32634176 (2020), 31307542 (2019)), ovarian cancer (PMID: 36169650 (2022)), breast cancer (PMID: 35449176 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), as well as in reportedly healthy individuals (PMID: 36243179 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000031 (4/129198 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 11, 2024

This missense variant replaces asparagine with serine at codon 112 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with mismatch DNA repair proficient endometrial cancer (PMID: 31307542) and several individuals affected with breast cancer (PMID: 29684080, 33471991; Lovejoy, et al. 2018). This variant has been identified in 7/282896 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. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The MSH6 p.Asn112Ser variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with triple negative breast cancer (Lovejoy 2018). The variant was also identified in dbSNP (ID: rs587779934) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 7 of 277252 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24034 chromosomes (freq: 0.00008), European in 4 of 126734 chromosomes (freq: 0.00003), East Asian in 1 of 18868 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Asn112 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;T;T;.;T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

.;T;T;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.22

T;T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.91

.;L;.;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.79

.;N;.;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.15

.;T;.;T;T;T

Sift4G

Benign

0.58

T;T;T;T;T;T

Polyphen

0.41

.;B;.;.;.;.

Vest4

0.47, 0.50

MutPred

0.57

.;Gain of glycosylation at N112 (P = 0.0346);.;.;.;.;

MVP

0.60

ClinPred

0.20

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.48

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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