2-47806284-A-T

Position:

• chr2-47806284-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_000179.3(MSH6):​c.3727A>T​(p.Thr1243Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 1,614,088 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:11
• Conservation: PhyloP100: 7.07

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]

FBXO11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34604505).
• BP6: Variant 2-47806284-A-T is Benign according to our data. Variant chr2-47806284-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127589.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=8, Benign=1}. Variant chr2-47806284-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000138 (21/152328) while in subpopulation SAS AF= 0.00187 (9/4820). AF 95% confidence interval is 0.000974. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3727A>T	p.Thr1243Ser	missense_variant	8/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3727A>T	p.Thr1243Ser	missense_variant	8/10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 251210 Hom.: 1 AF XY: 0.000383 AC XY: 52 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000168 AC: 246 AN: 1461760 Hom.: 2 Cov.: 33 AF XY: 0.000212 AC XY: 154 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 24, 2019	The MSH6 c.3727A>T; p.Thr1243Ser variant (rs147453999) is reported in the literature in individuals with hereditary cancer predisposition syndrome, ovarian cancer, or mesothelioma (Betti 2017, Pal 2012, Tsaousis 2019). This variant is also reported in ClinVar (Variation ID: 127589). It is found in the general South Asian population with an allele frequency of 0.1% (35/30614 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 1243 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Betti M et al. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett. 2017 Oct 1;405:38-45. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MSH6: BP1, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 12, 2024	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2020	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: 23047549, 23621914, 28687356, 26338694, 31159747) -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2021	Variant summary: MSH6 c.3727A>T (p.Thr1243Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251210 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7.7 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 South Asian origin. c.3727A>T has been reported in the literature in individuals with a variety of cancer types such as epithelial ovarian cancer (example, Pal_2012), kidney renal clear cell carcinoma in the TGCA cohort (Lu_2015), as a VUS in Malignant pleural mesothelioma (MPM) (example, Betti_2017), as a VUS in breast/ovarian cancer (example, Tsaousis_2019, Akcay_2020, Moradian_2021). 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. Fifteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=12). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 30, 2020	DNA sequence analysis of the MSH6 gene demonstrated a sequence change, c.3727A>T, in exon 8 that results in an amino acid change, p.Thr1243Ser. This sequence change has been described in the gnomAD database with a frequency of 0.11% in South Asian populations (dbSNP rs147453999). The p.Thr1243Ser change has been identified in an individual with mesothelioma and exposure to asbestos (PMID: 28687356). The p.Thr1243Ser change affects a highly conserved amino acid residue located in a domain of the MSH6 protein that is known to be functional. The p.Thr1243Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr1243Ser change remains unknown at this time. -

Lynch syndrome 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 09, 2024	- -

Lynch syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	- -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Thr1243Ser variant was identified in 2 of 3972 proband chromosomes (frequency: 0.001) from individuals or families with malignant pleural mesothelioma, epithelial ovarian cancer (Betti 2017, Pal 2012). The variant was also identified in dbSNP (ID: rs147453999) as “With other allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Color Genomics; as likely benign by Invitae, IGLCA), Clinvitae, COGR, MutDB, and the Insight Hereditary Tumors Database. The variant was not identified in Cosmic, UMD-LSDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 77 of 276950 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 7 of 6454 chromosomes (freq: 0.001), Latino in 21 of 34370 chromosomes (freq: 0.001), European in 14 of 126502 chromosomes (freq: 0.0001), and South Asian in 35 of 30782 chromosomes (freq: 0.001); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Thr1243 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In a study that integrated the prediction results of three in silico programs and two other structural properties, namely solvent accessibility and the change in the number of heavy atoms of amino acids in the MSH6 protein, the authors concluded the variant has an impact on the MSH6 protein (Terui 2013). 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. -

bilateral breast cancer Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Apr 08, 2020

ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A domain mutATP5 (V1127-1321R aa) functioning in ATPase activity. Hot-spot has 30 non-VUS coding variants (19 pathogenic and 11 benign), pathogenicity = 63.3%, proximity score 9.180 > threshold 2.472. PP3 Pathogenic Supporting: 7 pathogenic predictions from DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 4 benign predictions from DANN, EIGEN, MutationAssessor and REVEL. BS1 Benign Strong: GnomAD exomes South Asian allele frequency = 0.00114 > 0.000649 derived from the 3,884 clinically reported variants in gene MSH6 of which 739 PATH, 2,198 VUS and 947 benign. BP1 Benign Supporting: 85 out of 114 non-VUS missense variants in gene MSH6 are BEN = 74.6% > threshold of 51.0%, and 947 out of 3,884 clinically reported variants in gene MSH6 are BEN = 24.4% > threshold of 24.0%. BP6: Multiple reputable databases/clinical laboratories cite the variant with conflicting classifications "uncertain significance" or "likely benign." Therefore, it has been classified as a Variant of Uncertain Significance. -

Inherited ovarian cancer (without breast cancer) Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

May 08, 2024

BS1_Strong,BS2 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;.;T;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.8	.;.;.;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	.;D;.;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	.;D;.;D;T
Sift4G	Benign	0.11	T;T;T;D;T
Polyphen		0.95	.;.;.;P;.
Vest4		0.86
MVP		0.94
ClinPred		0.12	T
GERP RS		4.3
Varity_R		0.72
gMVP		0.81

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: rs147453999; hg19: chr2-48033423;