2-47806501-C-T

Variant names:

• chr2-47806501-C-T
• rs63750836
• NM_000179.3:c.3851C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS1

The NM_000179.3(MSH6):​c.3851C>T​(p.Thr1284Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,613,878 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:6
• Conservation: PhyloP100: 7.88

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 -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• BP6: Variant 2-47806501-C-T is Benign according to our data. Variant chr2-47806501-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89476.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=7}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000841 (123/1461776) while in subpopulation SAS AF= 0.000916 (79/86256). AF 95% confidence interval is 0.000753. There are 0 homozygotes in gnomad4_exome. There are 78 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3851C>T	p.Thr1284Met	missense_variant	Exon 9 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3851C>T	p.Thr1284Met	missense_variant	Exon 9 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 250814 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461776 Hom.: 0 Cov.: 35 AF XY: 0.000107 AC XY: 78 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74268

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 5 Uncertain:2 Benign:1

Mar 29, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Apr 06, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:1

Nov 08, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in individuals with a personal or family history of pancreatic cancer, rhabdomyosarcoma, a microsatellite stable (MSS) colon tumor, and/or other cancers (Chan et al., 1999; Yan et al., 2007; Chan et al., 2017; Young et al., 2018); Published functional studies demonstrate no damaging effect: subcellular localization and mismatch repair activity similar to wild type (Belvederesi et al., 2012; Drost et al., 2020); This variant is associated with the following publications: (PMID: 23621914, 17854147, 26333163, 10413423, 22851212, 29945567, 28878254, 31965077, 17531815, 21120944) -

Jun 29, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr1284Met variant in MSH6 has been reported in 2 individuals with colorectal cancer, 1 individual with sarcoma, and 1 individual with pancreatic cancer (Chan 1999 PMID: 10413423, Yan 2007 PMID: 17854147, Chan 2017 PMID: 28878254, Young 2018 PMID: 29945567). It has also been identified in 0.11% (35/30610) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide conflicting evidence regarding the role of this variant on protein function (Belvederesi 2012 PMID: 22851212, Terui 2013 PMID: 23621914, Niroula 2015 PMID: 26333163); however, these types of assays may not accurately represent biological function. In summary, while the clinical significance of this variant is uncertain, its frequency in combination with these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PP3. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Feb 15, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 13, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3_Moderate, BS1, BS3_Supporting c.3851C>T, located in exon 9 of the MSH6 gene, is predicted to result in the substitution of Thr by Met at codon 1284, p.(Thr1284Met). The variant allele was found in 35/30520 alleles, with a filter allele frequency of 0.085% at 95% confidence, within the South Asian population in the gnomAD v2.1.1 database (non-cancer data set) (BS1). Computational tools for this variant suggest no significant impact on splicing and predict a deleterious effect on protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.93 > 0.81) (PP3_moderate). It has been reported in a CIMRA assay with functional Odds for Pathogenicity 0.211 (≤ 0.48) (PMID: 31965077), and it has also shown nuclear expression similar to wild type (PMID: 22851212) (BS3_Supporting). This variant has been reported in two patients affected with colorectal and/or endometrial cancer, and one of these tumours showed microsatellite stability (PMIDs: 10413423, 17854147). In addition, this variant has been reported in ClinVar (5x likely benign, 7x uncertain significance), LOVD (7x uncertain significance) and in InSiGHT (as Class3: uncertain; Summary Justification: Insuficient evidence; 2013/09/05 v1.9) databases. Based on currently available information, the variant c.3851C>T should be considered a likely benign variant. -

Nov 08, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1284 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). A functional study reported that this variant has normal nuclear localization in transfected ex vivo cells (PMID: 22851212). This variant has been observed in an individual affected with microsatellite stable colorectal cancer and another individual affected with colorectal and endometrial cancer whose tumor showed the loss of MSH6 by immunohistochemistry (PMID: 10413423, 17854147, 18067074; InSiGHT database). This variant also has been observed in individuals affected with sporadic sarcomas, pancreatic cancer, or breast cancer (PMID: 28878254, 29945567, 32068069). This variant has been identified in 50/282196 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. -

Breast and/or ovarian cancer Uncertain:1

Aug 29, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Thr1284Met variant was identified in 2 of 312 proband chromosomes (frequency: 0.006) from individuals or families with colorectal cancer (Chan 1999, Yan 2007). The variant was also identified in the following databases: dbSNP (ID: rs63750836) as With Uncertain significance allele, ClinVar (classified as uncertain significance by InSight, Ambry Genetics, GenDx; classified as likely benign by Ivitae), Clinvitae (classified as uncertain significance by ClinVar), MutDB (unclassified), Insight Colon Cancer Gene Variant Database (4X class3), Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (4X). The variant was not identified in Cosmic, UMD-LSDB, databases. The variant was identified in control databases in 50 of 276776 chromosomes at a frequency of 0.000181 (Genome Aggregation Consortium Feb 27, 2017). The sub-cellular localization analysis of this variant suggested a proper MSH6 nuclear import (Belvederesi 2012). The p.Thr1284 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. The variant is located with the DNA mismatch repair protein MutS, C-terminal P-loop containing nucleoside triphosphate hydrolase DNA mismatch repair protein Msh6 functional domains. 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

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.3851C>T (p.Thr1284Met) variant in MSH6 gene has been reported previously in individuals in heterozygous state with MSH6-related susceptiblity to cancer (Yan et al. 2007; Chan et al. 2017; Young et al. 2018). The p.Thr1284Met variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance (multiple submissions). The amino acid change p.Thr1284Met in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 1284 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

not specified Benign:1

Nov 25, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.3851C>T (p.Thr1284Met) 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 0.00019 in 251304 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3851C>T has been reported in the literature in individuals affected with Lynch Syndrome, sporadic sarcoma, or pancreatic cancer (Chan_1999, Yan_2007, Belvederesi_2012, Chan_2017, Young_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (6x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.9	.;.;.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.4	.;D;.;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	.;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.91
MVP		0.98
ClinPred		0.50	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750836; hg19: chr2-48033640; COSMIC: COSV52277844; COSMIC: COSV52277844;