rs202066386

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM5PP3BP4_ModerateBP6

The NM_000179.3(MSH6):c.3758T>A(p.Val1253Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,156 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. V1253A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:3

Conservation

PhyloP100: 7.62

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 Uncertain_significance. Variant got 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47806313-AGT-AA is described in Lovd as [Pathogenic].

PP3

Multiple lines of computational evidence support a deleterious effect 5: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.17562485).

BP6

Variant 2-47806315-T-A is Benign according to our data. Variant chr2-47806315-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127591.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=11}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.3758T>A	p.Val1253Glu	missense_variant	8/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.3758T>A	p.Val1253Glu	missense_variant	8/10	1	NM_000179.3	P4	P52701-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251190

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.0000711

AC:

104

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727206

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:

0.000468

Gnomad4 NFE exome

AF:

0.0000639

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000609

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 18, 2022	The p.V1253E variant (also known as c.3758T>A), located in coding exon 8 of the MSH6 gene, results from a T to A substitution at nucleotide position 3758. The valine at codon 1253 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration has been reported in multiple cohorts of patients undergoing multigene panel testing, including individuals diagnosed with a Lynch syndrome-associated cancer and/or polyps (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Yehia L et al. PLoS Genet. 2018 04;14:e1007352; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20; Young EL et al. BMC Cancer. 2018 Jun;18:697). It was identified in a 70-year-old individual with microsatellite-stable, mismatch repair protein-proficient colorectal cancer (Kraus C et al. Int. J. Cancer. 2015 Mar;136:E559-68), as well as two patients, one with breast and the other with renal cancer, from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec;6:10086). Additionally, this alteration was identified in 1/2515 controls and 0/165 individuals with colorectal cancer and/or polyps (Rosenthal EA et al. Hum. Genet. 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This missense variant replaces valine with glutamic acid at codon 1253 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25142776, 25980754) and other non-Lynch or unspecified cancers (PMID: 26689913, 29684080, 31921681, 31391288), and in an unaffected individual (PMID: 31422574). This variant has also been identified in 42/282588 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	Feb 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2023	Variant summary: MSH6 c.3758T>A (p.Val1253Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251190 control chromosomes, predominantly at a frequency of 0.00023 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.62 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 Non-Finnish European origin. c.3758T>A has been reported in the literature in individuals affected with or being tested for Lynch Syndrome, as well as in patients with breast or ovarian cancer (e.g. Kraus_2015, Lu_2015, Young_2018, Yurgelun_2015, Tsaousis_2019, Morak_2019, Li_2020, Kraemer_2019, Oliver_2019, Dorling_2021, Pereira_2022). However, the variant was also identified in many healthy controls (e.g., Dorling_2021, Rosenthal_2018). These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One publication reports experimental evidence evaluating an impact on RNA splicing and found that the variant had no effect (e.g., Frederiksen_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31422574, 25142776, 31391288, 26689913, 31332305, 31921681, 23621914, 31159747, 29945567, 25980754, 34445333, 35980532, 29684080, 30267214, 33471991). Ten ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: VUS (n = 8) and likely benign (n = 2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 26, 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: This variant has been reported in one individual with CRC. MaxMAF is 0.09%. Classified as DM? in HGMD. Classified in ClinVar as VUS by Invitae, Ambry, GeneDx (2 stars). MAF is greater than or equal to disease prevalence -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal, ovarian, breast, or other cancers, as well as in unaffected control groups (PMID: 29684080, 25142776, 26689913, 29945567, 33471991, 34326862, 35980532); This variant is associated with the following publications: (PMID: 28166811, 22949387, 23621914, 25142776, doi:10.5923/j.bioinformatics.20160602.03, 29684080, 25980754, 29945567, 31159747, 26689913, 31422574, 31391288, 31332305, 31921681, 30267214, 34445333, 33471991, Giacomazzi2022[preprint], 17531815, 21120944, 35980532, 36461907, 34326862) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MSH6: BP1, BS1:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Lynch syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 12, 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. -

MSH6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2024

The MSH6 c.3758T>A variant is predicted to result in the amino acid substitution p.Val1253Glu. This variant has been reported with uncertain significance in individuals with colorectal, suspected Lynch syndrome, or breast cancer (Table 4, ID 48, Kraus et al. 2015. PubMed ID: 25142776; able S5, Li et al. 2020. PubMed ID: 31391288; Supplementary Data, Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991; Table S4, Bhai et al. 2021. PubMed ID: 34326862; Pereira et al. 2022. PubMed ID: 35980532). It was also reported as a variant of uncertain significance in a study of individuals with hereditary cancer syndromes, however specific clinical features were not noted (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant has also been reported in control populations (Supplementary Table 2, Rosenthal et al. 2018. PubMed ID: 30267214; Supplementary Data, Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.044% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127591/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces valine with glutamic acid at codon 1253 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25142776, 25980754) and other non-Lynch or unspecified cancers (PMID: 26689913, 29684080, 31921681, 31391288), and in an unaffected individual (PMID: 31422574). This variant has also been identified in 42/282588 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.Val1253Glu variant was identified in 1 of 304 proband chromosomes (frequency: 0.003) from individuals or families with colorectal cancer (Kraus 2014). The variant was also identified in dbSNP (ID: rs202066386) as "With Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, and three other submitters), and in UMD-LSDB. The variant was identified in control databases in 41 of 276934 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 5 of 6460 chromosomes (freq: 0.0008), Latino in 1 of 34382 chromosomes (freq: 0.00002), European in 25 of 126474 chromosomes (freq: 0.0002), Finnish in 10 of 25788 chromosomes (freq: 0.0004); it was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. An experimental study on predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein identified the p.Val1253Glu has an impact on MSH6 (Terui 2013). The p.Val1253 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of 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. -

Endometrial carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.18

MetaSVM

Uncertain

0.53

MutationTaster

Benign

1.0

D;D;D;D

Sift4G

Benign

0.11

Vest4

0.51

MVP

0.94

ClinPred

0.54

GERP RS

5.5

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