2-47798909-C-G

Variant names:

• chr2-47798909-C-G
• rs544222338
• NM_000179.3:c.926C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000179.3(MSH6):​c.926C>G​(p.Ser309Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,614,160 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. S309Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (4 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 1.87
• Publications: 14 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010223001).
• BP6: Variant 2-47798909-C-G is Benign according to our data. Variant chr2-47798909-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127607.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000788 (12/152280) while in subpopulation SAS AF = 0.00187 (9/4820). AF 95% confidence interval is 0.000974. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.926C>G	p.Ser309Cys	missense_variant	Exon 4 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.926C>G	p.Ser309Cys	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000302 AC: 76 AN: 251308 AF XY: 0.000464

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.000176 AC: 257 AN: 1461880 Hom.: 4 Cov.: 34 AF XY: 0.000267 AC XY: 194 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00272 AC: 235 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112004

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Feb 09, 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; This variant is associated with the following publications: (PMID: 28873162, 31307542, 21437237, 37013556, 35449176, 36243179)

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6: BS1

not specified Benign:2

May 19, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 06, 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.926C>G (p.Ser309Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251308 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Non-Polyposis Colon Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.926C>G has been reported in the literature in individual(s) affected with advanced cancer (Mandelker_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as likely benign.

Hereditary cancer-predisposing syndrome Benign:2

Apr 07, 2021

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.

Nov 04, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6-related disorder Uncertain:1

Aug 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH6 c.926C>G variant is predicted to result in the amino acid substitution p.Ser309Cys. This variant has been reported in at least one individual with advanced cancer (Mandelker et al. 2017. PubMed ID: 28873162) and in a patient with ovarian cancer (Prokofyeva et al. 2023. PubMed ID: 37013556). This variant was also reported in two individuals with endometrial cancer; however, immunohistochemistry of the tumor found one individual had normal MSH6 staining while MSH6 was absent in the other (Chao et al. 2019. PubMed ID: 31307542). This variant is reported in 0.24% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026048-C-G) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127607/). At this time, while we suspect this variant could be benign (based on minor allele frequency) the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Lynch syndrome 5 Benign:1

Dec 20, 2024

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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Carcinoma of colon Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH6 p.Ser309Cys variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals with advanced cancer (Mandelker 2017). The variant was identified in dbSNP (rs544222338) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics and likely benign by Color and Invitae) and UMD-LSDB (observed 1x). The variant was identified in control databases in 75 of 277,020 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,004 chromosomes (freq: 0.00004), European in 3 of 126,576 chromosomes (freq: 0.00002) and South Asian in 71 of 30,780 chromosomes (freq: 0.002). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Ser309Cys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Ovarian cancer Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 23, 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	Benign	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;.;D;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.0	.;T;T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.0	.;.;L;.;.
PhyloP100		1.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.0	.;N;D;.;N
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;T;.;T
Sift4G	Uncertain	0.0080	D;T;T;T;D
Vest4		0.31
ClinPred		0.075	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.12
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs544222338; hg19: chr2-48026048; COSMIC: COSV99029743;