rs564434147

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6

The NM_000179.3(MSH6):c.4004A>C(p.Glu1335Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,590,584 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1335D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 7.23

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 16 uncertain in NM_000179.3

BP6

Variant 2-47806781-A-C is Benign according to our data. Variant chr2-47806781-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141327.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.4004A>C	p.Glu1335Ala	missense_variant, splice_region_variant	10/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.4004A>C	p.Glu1335Ala	missense_variant, splice_region_variant	10/10	1	NM_000179.3	P4	P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

149114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000267

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000629

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000486

GnomAD3 exomes

AF:

0.0000866

AC:

AN:

242576

Hom.:

AF XY:

0.0000915

AC XY:

AN XY:

131154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000212

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000314

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000451

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1441360

Hom.:

Cov.:

AF XY:

0.0000697

AC XY:

AN XY:

717184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000187

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000264

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000536

AC:

AN:

149224

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

72806

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000267

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000630

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000481

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2023	The p.E1335A variant (also known as c.4004A>C), located in coding exon 10 of the MSH6 gene, results from an A to C substitution at nucleotide position 4004. The glutamic acid at codon 1335 is replaced by alanine, an amino acid with dissimilar properties. This variant was reported in one family that met Amsterdam criteria and segregated with disease. The proband was diagnosed with colon cancer at age 42; however, tumor testing showed wild-type BRAF analysis, microsatellite stability, and normal IHC staining (Pérez-Cabornero L et al. J Mol Diagn. 2013 May;15(3):380-90). This alteration has also been reported as a variant of unknown significance, detected in a low-grade malignant astrocytoma that showed microsatellite stability and loss of staining for MLH1, MSH2, and MSH6 on IHC (Rodríguez-Hernández I et al. PLoS One. 2013 Sep 20;8(9):e76401). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513; Cock-Rada AM et al. Fam Cancer, 2018 Jan;17:23-30; Nikitin AG et al. Front Oncol. 2020 May;10:666; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence for this variant is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces glutamic acid with alanine at codon 1335 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 individuals affected with colorectal cancer (PMID: 23523604), astrocytoma (PMID: 24073290), breast and/or ovarian cancer (PMID: 28528518, 32547938) or suspected of having Lynch syndrome (PMID: 31391288). In a large breast cancer case control study, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991). This variant has also been identified in 22/271900 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. -

Lynch syndrome 5

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 29, 2023	This variant is considered likely 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: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 25, 2016	- -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Glu1335Ala variant was identified in 3 of 680 proband chromosomes (frequency: 0.004) from individuals or families with Lynch syndrome, astrocytoma, and breast or ovarian cancer and was not identified in 694 control chromosomes from healthy individuals (Perez-Cabornero 2013, Rodriguez-Hernandez 2013, Cock-Rada 2018). The variant was also identified in dbSNP (ID: rs564434147 as "With Uncertain significance allele"), ClinVar (6x as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx, Color Genomics, and EGL Genetic), and UMD-LSDB (1x as unclassified variant). The variant was not identified in the COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 18 of 237668 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 7 of 32242 chromosomes (freq: 0.0002), European Non-Finnish in 2 of 108812 chromosomes (freq: 0.00008), and South Asian in 9 of 28764 chromosomes (freq: 0.0003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1335 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, HumanSpliceFinder) 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	This variant is associated with the following publications: (PMID: 23523604, 28528518, 24073290) -

MSH6-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

The MSH6 c.4004A>C variant is predicted to result in the amino acid substitution p.Glu1335Ala. This variant has been reported in individuals with a history of Lynch syndrome, astrocytoma, and breast and/or ovarian cancer (Rodríguez-Hernández et al. 2013. PubMed ID: 24073290; Pérez-Cabornero et al. 2013. PubMed ID: 23523604; Cock-Rada et al. 2018. PubMed ID: 28528518). This variant is reported in 0.031% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141327/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1335 of the MSH6 protein (p.Glu1335Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal cancer, astrocytoma, or breast and/or ovarian cancers (PMID: 23523604, 24073290, 28528518, 30306255, 32547938). ClinVar contains an entry for this variant (Variation ID: 141327). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Endometrial carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 13, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 26, 2024

Variant summary: MSH6 c.4004A>C (p.Glu1335Ala) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 1590584 control chromosomes, predominantly at a frequency of 0.00036 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch syndrome (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.4004A>C has been reported in the literature in individuals undergoing multigene panel testing for hereditary cancers such as Lynch, low grade astrocytoma and breast (example, Perez-Cabornero_2013, Rodriguez-Hernandez_2013, Cock-Rada_2017, Nikitin_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least three co-occurrences with other pathogenic variant(s) have been reported in the literature and observed at our laboratory (BRCA1 c.5266dupC, p.Gln1756Profs, Nikitin_2020; PALB2 c.1317delG, p.Phe440fs, internal testing; CDH1 c.537delA , p.Lys179Asnfs*36, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A study that computed a tumor characteristic likelihood ratio (TCLR) in combination with in-silico predictors and multifactorial variant prediction (MVP) model including allele frequency, co-occurrence, co-segregation, clinical and family history information classified this variant a "likely benign". The following publications have been ascertained in the context of this evaluation (PMID: 30306255, 28528518, 31391288, 32547938, 23523604, 24073290). ClinVar contains an entry for this variant (Variation ID: 141327). Some submitters cite overlapping but not identical evidences utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.10

.;.;T;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.069

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.090

T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.6

.;.;.;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.82

.;N;.;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.63

.;T;.;T;T

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.012

.;.;.;B;.

Vest4

0.51

MutPred

0.42

.;.;.;Gain of MoRF binding (P = 0.0363);.;

MVP

0.88

ClinPred

0.12

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 3

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