rs587782109

Variant names:

• chr2-47806482-C-A
• rs587782109
• NM_000179.3:c.3832C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47806482-C-A
• chr2-47806482-C-G
• chr2-47806482-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000179.3(MSH6):​c.3832C>A​(p.Pro1278Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,613,780 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. P1278L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 6.10
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 65 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.19855991).
• BP6: Variant 2-47806482-C-A is Benign according to our data. Variant chr2-47806482-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141916.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3832C>A	p.Pro1278Thr	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.3832C>A	p.Pro1278Thr	missense_variant	Exon 9 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 250902 AF XY: 0.0000958

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461792 Hom.: 0 Cov.: 35 AF XY: 0.0000399 AC XY: 29 AN XY: 727198

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000470 AC: 21 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111970

Other (OTH) AF: 0.0000662 AC: 4 AN: 60388

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74222

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000113 Hom.: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:2

Apr 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with threonine at codon 1278 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 31391288, 33359728), as well as an individual not affected with cancer with a family history of various cancers (PMID: 30883245). This variant also has been reported in three individuals affected with breast and/or ovarian cancer, in which two carriers also had a pathogenic CHEK2 covariant (PMID: 25186627). This variant has been identified in 26/250902 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. -

Sep 11, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Jan 22, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 07, 2020

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. -

Oct 09, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4 c.3832C>A located in exon 9 of the MSH6 gene, is predicted to result in the substitution of proline by threonine at codon 1278, p.(Pro1278Thr).This variant is found in 16/35070, with a filter allele frequency of 0.029% in the gnomAD v2.1.1 database, Latino non-cancer data set. (BS1). Computational tools for this variant suggests no significant impact on splicing and does not affect the protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.005)(BP4). To our knowledge, functional studies have not been reported for this variant. In addition, the variant has been reported in the ClinVar database (5x uncertain significance, 3x likely benign) but it has not been identified neither LOVD nor InSiGHT databases. Based on currently available information, the variant c.3832C>A is classified as a likely benign variant according to ACMG guidelines. -

not provided Uncertain:3

Jul 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2025

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; Observed in individuals with a personal or family history of breast, prostate, or colorectal cancer (PMID: 25186627, 30883245, 33359728); This variant is associated with the following publications: (PMID: 30883245, 31391288, 25186627, 33359728, 36845387, 17531815, 21120944) -

Sep 20, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.3832C>A (p.Pro1278Thr) variant has been reported in the published literature in in individuals with breast cancer (PMID: 25186627 (2015)), colorectal cancer (PMID: 33359728 (2022)), pancreatic cancer (PMID: 30883245 (2019)), and a Lynch syndrome associated cancer (PMID: 31391288 (2020)). The frequency of this variant in the general population, 0.0006 (6/10074 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 a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded a prediction that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Lynch syndrome Uncertain:1 Benign:1

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with threonine at codon 1278 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 31391288, 33359728), as well as an individual not affected with cancer with a family history of various cancers (PMID: 30883245). This variant also has been reported in three individuals affected with breast and/or ovarian cancer, in which two carriers also had a pathogenic CHEK2 covariant (PMID: 25186627). This variant has been identified in 26/250902 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. -

Feb 15, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Sep 16, 2020

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.3832C>A (p.Pro1278Thr) 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 0.0001 in 250902 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3-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 Latino origin. c.3832C>A has been reported in the literature in individuals affected with cancer including breast and ovarian cancer (e.g. Tung 2015, Li_2020) but it was also reported in an individual with no personal history of cancer who was above the average age of onset for Hereditary Nonpolyposis Colorectal Cancer (Abe_2019). Co-occurrences with pathogenic variants have been reported in the literature in individuals affected with breast and ovarian cancer (BRCA1 c.3759_3760delTA, p.Lys1254GlufsX12; CHEK2 c.1283C>T, p.Ser428Phe) (Tung_2015) and also via internal testing (MSH6 c.2150_2153delTCAG, p.V717fsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Lynch syndrome 5 Benign:1

Jan 08, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered 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: 27363726]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 29, 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;.;T;D;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.88	.;.;.;L;.
PhyloP100		6.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.7	.;D;.;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.018	.;D;.;D;T
Sift4G	Benign	0.088	T;T;T;T;T
Polyphen		0.94	.;.;.;P;.
Vest4		0.51
MutPred		0.36		.;.;.;Gain of phosphorylation at P1278 (P = 0.0554);.;
MVP		0.91
ClinPred		0.24	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.67
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs587782109; hg19: chr2-48033621;