2-47795968-C-T

Variant names:

• chr2-47795968-C-T
• rs730881813
• NM_000179.3:c.532C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_000179.3(MSH6):​c.532C>T​(p.Arg178Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R178L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 0.794
• Publications: 11 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11416224).
• BP6: Variant 2-47795968-C-T is Benign according to our data. Variant chr2-47795968-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 182656.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000328 (48/1461838) while in subpopulation EAS AF = 0.000731 (29/39698). AF 95% confidence interval is 0.000522. There are 0 homozygotes in GnomAdExome4. There are 20 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.532C>T	p.Arg178Cys	missense	Exon 3 of 10	NP_000170.1
	MSH6	NM_001281494.2		c.-371C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	NP_001268423.1
	MSH6	NM_001406814.1		c.-463C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001393743.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.532C>T	p.Arg178Cys	missense	Exon 3 of 10	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.458-2643C>T		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000700002.1		c.532C>T	p.Arg178Cys	missense	Exon 3 of 10	ENSP00000514750.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251442 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727228

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: 26134

East Asian (EAS) AF: 0.000731 AC: 29 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111962

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152102 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Nov 01, 2018

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 25, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 178 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with pancreatic, ovarian, colorectal cancer, or Lynch syndrome (PMID: 23047549, 24100870, 31386297, 32973888, 32980694), as well as in healthy control individuals (PMID: 32980694). In one individual affected with colorectal cancer, this variant co-occurred with a pathogenic MSH2 variant (PMID: 24100870). In a large colorectal cancer case-control study, this variant was reported in 28/12503 cases & 36/23705 controls (PMID: 33309985). This variant has also been identified in 6/282830 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.

May 21, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Oct 06, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4, BP5 c.532C>T, located in exon 3 of the MSH6 gene, is predicted to result in the substitution of Arginine by Cysteine at codon 178, p.(Arg178Cys). This variant is found in 6/268298 alleles at a frequency of 0.0022% in the gnomAD v2.1.1 database, non-cancer dataset. 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: 0.016) (BP4). To our knowledge, functional studies have not been reported for this variant. c.532C>T has been identified in CRC patients whose tumors did not show exclusive MSH6 loss expression pattern (PMID: 24100870) (BP5). It has also been identified in a patients with ovarian cancer (PMID: 2304754, data from our clinical cohort of patients) and other cancer patients. In a colorectal cancer case-control study, the c.532C>T variant has been found at a frequency of 0.22% in cases (28/12475) and a at a frequency of 0,15% in controls (36/23669) (PMID: 33309985). This variant has been reported in the ClinVar database (1x benign, 2x likely benign, 8x uncertain significance) and in the LOVD database (1x uncertain significance, 2x NA). It has not been classified in InSiGHT database. At present ClinVar does not describe pathogenic or likely pathogenic missense variants in this codon. Based on the currently available information, c.532C>T is classified as a likely benign variant according to ClinGen-MMR draft Guidelines version 3.1.

Lynch syndrome 5 Uncertain:2

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.532C>T(p.Arg178Cys) variant in MSH6 gene has been reported previously in heterozygous state in individual(s) affected with Lynch syndrome (LS) (Kiyozumi et al., 2019). This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database with varying interpretation: Benign / Likely Benign / Uncertain Significance (multiple submitters). The amino acid Arg at position 178 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg178Cys in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Probably damaging, SIFT - Tolerated, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance.

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:2

Aug 24, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 23047549 (2012)), breast cancer (PMIDs: 35449176 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)), colorectal cancer (PMIDs: 24100870 (2013), 31386297 (2019), 33309985 (2020)), acute myeloid leukemia (PMID: 31470354 (2019)), and biliary tract cancer (PMID: 36243179 (2022)). It has also been reported in healthy individuals (PMIDs: 36243179 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). The frequency of this variant in the general population, 0.00025 (5/19952 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Aug 05, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or ovarian cancer (Pal 2012, Terui 2013, Kiyozumi 2019); This variant is associated with the following publications: (PMID: 23047549, 24100870, 31386297, 31470354)

Lynch syndrome Uncertain:1

Dec 18, 2023

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 arginine with cysteine at codon 178 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with pancreatic, ovarian, colorectal cancer, or Lynch syndrome (PMID: 23047549, 24100870, 31386297, 32973888, 32980694), as well as in healthy control individuals (PMID: 32980694). In one individual affected with colorectal cancer, this variant co-occurred with a pathogenic MSH2 variant (PMID: 24100870). In a large colorectal cancer case-control study, this variant was reported in 28/12503 cases & 36/23705 controls (PMID: 33309985). This variant has also been identified in 6/282830 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.

Hereditary breast ovarian cancer syndrome Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Endometrial carcinoma Uncertain:1

Oct 19, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Feb 04, 2025

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.532C>T (p.Arg178Cys) results in a non-conservative amino acid change located in the PWWP domain (IPR000313) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 1613940 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014). c.532C>T has been reported in the literature in individuals affected with colorectal- and ovarian cancer (Pal_2012, Terui_2013, Kiyozumi_2019). However, one of the associated tumors was reported to be microsatellite stable, while another tumor showed the loss of MLH1 and PMS2 (Kiyozumi_2019). In addition, a co-occurrence with another (likely) pathogenic variant has been also noted (MSH2 c.1915C>T (p.His639Tyr); Terui_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29654263, 31386297, 23047549, 24100870). ClinVar contains an entry for this variant (Variation ID: 182656). Based on the evidence outlined above, the variant was classified as likely benign.

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.79
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Benign	0.078	T
Sift4G	Benign	0.068	T
Polyphen		0.97	D
Vest4		0.43
MutPred		0.41		Loss of MoRF binding (P = 0.0014)
MVP		0.71
ClinPred		0.44	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.32
Mutation Taster		=90/10	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: rs730881813; hg19: chr2-48023107;