rs63751328

Variant names:

• chr2-47805638-G-A
• rs63751328
• NM_000179.3:c.3577G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47805638-G-A
• chr2-47805638-G-C
• chr2-47805638-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000179.3(MSH6):​c.3577G>A​(p.Glu1193Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1193A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.36
• 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 57 uncertain in NM_000179.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47805639-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3296347.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 2-47805638-G-A is Pathogenic according to our data. Variant chr2-47805638-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 89422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3577G>A	p.Glu1193Lys	missense_variant	Exon 7 of 10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3577G>A	p.Glu1193Lys	missense_variant	Exon 7 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000536 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 1193 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). Functional studies have shown that this variant protein results in impaired DNA mismatch repair activity and reduced association with the MSH2 protein (PMID: 15354210). Another functional study has shown that the equivalent variant protein (p.Glu1191Lys) in mice also results in impaired DNA mismatch repair activity (PMID: 28531214). This variant has been reported in two individuals affected with endometrial cancer (PMID: 15354210, 16885385, 28531214), with microsatellite instability and/or loss of MSH6 protein expression reported in tumor samples. This variant has been reported in individuals affected with clinical features of Lynch syndrome (ClinVar SCV001492013.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 07, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1193K variant (also known as c.3577G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3577. The glutamic acid at codon 1193 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in two unrelated individuals diagnosed with endometrial cancer at ages 59 and 60, respectively, whose tumors showed high microsatellite instability (MSI-H) with loss of MSH6 staining on immunohistochemistry (IHC) (Kariola R et al. Br. J. Cancer, 2004 Oct;91:1287-92; Belvederesi L et al. Fam. Cancer. 2012 Dec;11:675-80). An in vivo mismatch repair (MMR) assay demonstrated that the E1193K variant displayed complete MMR deficiency at 0%. Additionally, a co-immunoprecipitation assay showed that the E1193K protein co-precipitated much less MSH2 compared to wildtype MSH6, suggesting interference in the heterodimerization between the MSH2 and MSH6 proteins (Kariola R et al. Br. J. Cancer. 2004 Oct;91:1287-92; Hampel H et al. Cancer Res. 2006 Aug;66:7810-7). In another study, the mouse equivalent of this variant was detected in a functional genetic screen and was shown to abrogate MMR activity (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). Based on an internal structural assessment, this alteration destabilizes the ATPase domain (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Lynch syndrome 5 Pathogenic:1

Aug 24, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 28531214, 15354210]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Apr 04, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH6 c.3577G>A (p.Glu1193Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249974 control chromosomes. c.3577G>A has been reported in the literature in individuals affected with endometrial cancer showing microsatellite instability and loss of MSH6 expression (Kariola_2004, Hampel_2006). These data indicate that the variant is likely associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function, showing a loss of MMR activity and disruption of heterodimerisation with MSH2 (Kariola_2004, Houlleberghs_2017). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch syndrome Pathogenic:1

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 1193 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). Functional studies have shown that this variant protein results in impaired DNA mismatch repair activity and reduced association with the MSH2 protein (PMID: 15354210). Another functional study has shown that the equivalent variant protein (p.Glu1191Lys) in mice also results in impaired DNA mismatch repair activity (PMID: 28531214). This variant has been reported in two individuals affected with endometrial cancer (PMID: 15354210, 16885385, 28531214), with microsatellite instability and/or loss of MSH6 protein expression reported in tumor samples. This variant has been reported in individuals affected with clinical features of Lynch syndrome (ClinVar SCV001492013.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Nov 16, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1193 of the MSH6 protein (p.Glu1193Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 15354210, 16885385; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 89422). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MSH6 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 15354210, 28531214). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Endometrial carcinoma Pathogenic:1

Dec 14, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	.;.;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	.;.;.;H;.
PhyloP100		9.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.98
MVP		0.99
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs63751328; hg19: chr2-48032777;