2-47799491-C-G

Variant names:

• chr2-47799491-C-G
• rs63750897
• NM_000179.3:c.1508C>G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):​c.1508C>G​(p.Ser503Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,976 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 Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely benign reviewed by expert panel B:29
• Conservation: PhyloP100: 3.31

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11110157).
• BP6: Variant 2-47799491-C-G is Benign according to our data. Variant chr2-47799491-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 89198.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47799491-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000546 (83/152118) while in subpopulation NFE AF= 0.00109 (74/68022). AF 95% confidence interval is 0.000888. There are 0 homozygotes in gnomad4. There are 40 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 rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1508C>G	p.Ser503Cys	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.1508C>G	p.Ser503Cys	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000617 AC: 155 AN: 251204 Hom.: 0 AF XY: 0.000641 AC XY: 87 AN XY: 135758

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: 0.0000462

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00123 AC: 1791 AN: 1461858 Hom.: 2 Cov.: 34 AF XY: 0.00114 AC XY: 829 AN XY: 727230

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000546 AC: 83 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74312

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000536

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.00125

EpiControl AF: 0.00166

ClinVar

Significance: Likely benign

Submissions summary: Benign:29

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:11

Jan 26, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MSH6 c.1508C>G (p.Ser503Cys) variant, located in the DNA mismatch repair protein MutS-like, N-terminal domain (via InterPro), causes a missense change involving a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools (SNPs&GO not captured due to low reliability index). The variant of interest was observed in the large and broad control population of ExAC with an allele frequency of 76/121318 (1/1596), predominantly in the European (Non-Finnish) cohort, 76/66712 (1/877), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, this is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. Multiple publications have cited the variant in affected individuals with HNPCC or HNPCC-related cancer with limited information (i.e. there is lack of co-occurrence and cosegregation information), although multiple authors have classified the variant as "benign" and reported presence of MSH6 protein expression in tumors of the CRC patients carrying this variant. In addition, a functional study (Drost_2011) reports the variant to have comparable MMR activity to that of wild-type. Furthermore, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign/benign. Therefore, the variant of interest has been classified as Benign. -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH6: BP1, BS3:Supporting, BS1 -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 21, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22102614, 18566915, 18033691, 24113346, 27028851, 16010685, 20176959, 19924528, 23621914, 22495361, 15340264, 14871975, 18269114, 23047549, 10508506, 28608266, 27273229, 26483394, 22006311) -

not specified Benign:4

Nov 05, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 29, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Sep 15, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Jan 01, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Lynch syndrome 5 Benign:3

Apr 21, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Lynch syndrome Benign:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 Benign:1

Mar 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Carcinoma of colon Benign:1

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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.Ser503Cys variant was identified in 12 of 9676 proband chromosomes (frequency: 0.0012) from Dutch, Korean, Scottish, and Danish individuals or families with hereditary and non-hereditary breast and colon cancer; the variant was present in 3 of 3752 control chromosomes (frequency: 0.001) from healthy individuals (Wijnen 1999, Kim 2004, Barneston 2008, Nilbert 2009, de Jong 2004). The variant was also identified in the following databases: dbSNP (ID: rs63750897) as “With other allele”, ClinVar (9x, as likely benign by Insight, GeneDx, Pathway Genomics, Color Genomics, COGR, ARUP, and Benign by EGL Genetic Diagnostics, Invitae and Ambry Genetics), Clinvitae (4x as likely benign and benign by ClinVar and EmvClass), COGR (as likely benign), UMD-LSDB (6 records, as neutral), Insight Colon Cancer Gene Variant Database (18x, as class 2), Mismatch Repair Genes Variant Database (5x), Insight Hereditary Tumors Database (18x, as likely benign). The variant was not identified in Cosmic, MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 178 of 276920 chromosomes at a frequency of 0.0006 in the following populations: African in 2 of 24028 chromosomes (freq. 0.00008), other in 2 of 6462 chromosomes (freq. 0.0003), Latino in 2 of 34386 chromosomes (freq. 0.00006), European non-Finnish in 171 of 126466 chromosomes (freq. 0.001), and European Finnish in 1 of 25790 chromosomes (freq. 0.00004), but was not seen in Ashkenazi Jewish, East Asian or South Asian populations (Genome Aggregation Consortium Feb 27, 2017). The p.Ser503Cys residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional studies on a yeast mutator assay using equivalent mutations at analogous chromosomal positions to assess mismatch repair (MMR) activity, found that the variant showed no significant difference between mutant and wildtype mutation rates (Martinez 2010). An additional functional assay measuring MMR mediated repair of a G-T mismatch engineered plasmid showed the variant to be MMR proficient (Drost 2012). The use of CoDP (Combination of different properties), a bioinformatics tool integrating prediction results of 3 in silico models and 2 structural properties, classified the variant as unlikely to be Lynch syndrome (or a carrier with a nonpathogenic variant), as it demonstrated MSS and showed normal expression of MSH6 (Terui 2013). 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. -

Breast and/or ovarian cancer Benign:1

Feb 23, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1

Oct 30, 2014

Pathway Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;.;D;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.7	.;.;L;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	.;D;D;.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	.;D;D;.;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.33
MVP		0.96
ClinPred		0.15	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.44

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: rs63750897; hg19: chr2-48026630; COSMIC: COSV104579282; COSMIC: COSV104579282;