rs200938360

chr2-47799347-A-Cchr2-47799347-A-Gchr2-47799347-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000179.3(MSH6):c.1364A>C(p.Asn455Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. N455K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 2.88

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]

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]

ACMG classification

Verdict is Likely_benign. 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 1 benign, 17 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.14166194).
• BP6: Variant 2-47799347-A-C is Benign according to our data. Variant chr2-47799347-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142181.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.1364A>C	p.Asn455Thr	missense_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.1364A>C	p.Asn455Thr	missense_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251056 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135692

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461760 Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000661 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2022	The p.N455T variant (also known as c.1364A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 1364. The asparagine at codon 455 is replaced by threonine, an amino acid with similar properties. This alteration was described in individuals with bladder cancer, head and neck squamous cell carcinoma, and Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (Shirts BH et al. Genet. Med. 2016 10;18:974-81; Lu C et al. Nat Commun. 2015 Dec;6:10086; Yehia L et al. PLoS Genet. 2018 04;14:e1007352). It was detected as a secondary finding in 1/571 patients ascertained for atherosclerosis phenotypes and in 1/345 individuals at high risk for pancreatic cancer who tested negative for germline mutations in pancreatic susceptibility genes (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108; Abe T et al. J. Clin. Oncol. 2019 05;37:1070-1080). It was also detected in 1/2512 control individuals from a healthy population database and in 0/165 colorectal cancer and/or polyposis patients (Rosenthal EA et al. Hum. Genet. 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	curation	Sema4, Sema4	Jun 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 14, 2016	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pancreatic, bladder, thyroid, and head and neck cancer (Lu et al., 2015; Shirts et al., 2016; Yehia et al., 2018; Abe et al., 2019); This variant is associated with the following publications: (PMID: 26689913, 23621914, 22703879, 26845104, 28873162, 29684080, 30883245, 21120944, 17531815) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 31, 2023	In the published literature, this variant has been reported in individuals with head and neck squamous cell carcinoma (PMID: 26689913 (2015)), bladder cancer (PMID: 26845104 (2016)), pancreatic cancer (PMID: 30883245 (2019)), and thyroid cancer and melanoma (PMID: 32885271 (2021)). This variant has also been observed in an individual with no cancer history (PMID: 22703879 (2012)). The frequency of this variant in the general population, 0.00079 (8/10070 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Lynch syndrome 5 Uncertain:1 Benign:1

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	Nov 17, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 11, 2023

Variant summary: MSH6 c.1364A>C (p.Asn455Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain 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 6e-05 in 251056 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (6e-05 vs 0.00014), allowing no conclusion about variant significance. c.1364A>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer or other type of cancer (examples: Shirts_2015, Lu_2015, Abe_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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: 30883245, 22703879, 26689913, 26845104, 23621914). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

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.Asn455Thr variant was identified in 1 of 1142 control chromosomes (frequency: 0.001) in individuals with atherosclerosis phenotypes undergoing secondary (incidental) variant detection by exome sequencing (Johnston 2012_ 22703879). A bioinformatic tool, CoDP ((Combination of the Different Properties), that integrates 3 prediction models (MAPP, PolyPhen-2 and SIFT) and 2 structural properties, found that the variant had no impact on the MSH6 protein (Terui 2013 23621914). The variant was also identified in dbSNP (ID: rs200938360) “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, Invitae, University of Washington, GeneDx, and Counsyl), Clinvitae (4x as uncertain significance), LOVD 3.0 (1x), and in control databases in 13 of 245818 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15302 chromosomes (freq: 0.00007), Latino in 4 of 33544 chromosomes (freq: 0.0001), European Non-Finnish in 1 of 111452 chromosomes (freq: 0.000009), Ashkenazi Jewish in 7 of 9842 chromosomes (freq: 0.0007), while not observed in the Other, East Asian, European Finnish and South Asian populations. The variant was not identified in Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The p.Asn455 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 the variant Thr impacts the protein; this information is not predictive enough to rule out 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. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	17
Dann	Benign	0.89
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.0030	.;.;B;.;.
Vest4		0.14
MVP		0.81
ClinPred		0.075	T
GERP RS		4.0
Varity_R		0.21
gMVP		0.28

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

Other links and lift over

dbSNP: rs200938360; hg19: chr2-48026486;