rs748165218

chr2-47799389-A-Gchr2-47799389-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3_Moderate

The NM_000179.3(MSH6):c.1406A>G(p.Tyr469Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,852 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y469F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 5.51

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 Uncertain_significance. Variant got 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47799389-A-TG is described in ClinVar as [Pathogenic]. Clinvar id is 2673792.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.1406A>G	p.Tyr469Cys	missense_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.1406A>G	p.Tyr469Cys	missense_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251178 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135748

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: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461852 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33007869, 17531815, 21120944, 29192238, 35264596, 36243179, 32980694, 32459922) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 01, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 33007869 (2020)), lung cancer (PMID: 35712480 (2022)), and in healthy controls (PMID: 36243179 (2022)). In a breast cancer association study, this variant was observed in 3 breast cancer cases and in 1 control individual (see LOVD (http://databases.lovd.nl/shared/genes/MSH6) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000012 (3/251178 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 08-22-2015 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Lynch syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 16, 2022	This missense variant replaces tyrosine with cysteine at codon 469 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 32980694), or breast cancer (PMID: 33007869), however this individual also has a pathogenic TP53 variant that likely accounts for the disease. This variant has been identified in 3/251178 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces tyrosine with cysteine at codon 469 of the MSH6 protein. Computational prediction 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 an individual affected with breast cancer (PMID: 33007869), however, this individual also had a pathogenic TP53 variant that likely accounts for the disease. In a pancreatic cancer case-control study, this variant was observed in one affected individual and two unaffected controls (PMID: 32980694). This variant has been identified in 3/251178 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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	clinical testing	Ambry Genetics	May 12, 2022	The p.Y469C variant (also known as c.1406A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1406. The tyrosine at codon 469 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in a Japanese population cohort of 2049 individuals who underwent whole-genome sequencing (Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This alteration was also observed in a cohort of 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium (Lee YR et al. N Engl J Med, 2020 05;382:2103-2116). This amino acid position is not well 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. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 469 of the MSH6 protein (p.Tyr469Cys). This variant is present in population databases (rs748165218, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 231340). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.017	D;D;D;D;D
Polyphen		0.99	.;.;D;.;.
Vest4		0.56
MutPred		0.84		.;.;Loss of phosphorylation at Y469 (P = 0.0714);.;.;
MVP		0.98
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.77
gMVP		0.74

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: rs748165218; hg19: chr2-48026528;