rs587779300

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_001406800.1(MSH6):​c.3961_3963delAGA​(p.Arg1321del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MSH6
NM_001406800.1 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15

Conservation

PhyloP100: 9.28
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001406800.1. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH6NM_000179.3 linkc.3974_3976delAGA p.Lys1325del disruptive_inframe_deletion Exon 9 of 10 ENST00000234420.11 NP_000170.1 P52701-1Q3SWU9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkc.3974_3976delAGA p.Lys1325del disruptive_inframe_deletion Exon 9 of 10 1 NM_000179.3 ENSP00000234420.5 P52701-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460220
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
726462
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152000
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74220
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lynch syndrome 5 Uncertain:3
Dec 31, 2015
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 29, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:3
Apr 22, 2024
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 31, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant causes the in-frame deletion of lysine 1325 in the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a homozygous carrier affected with colorectal and lung cancer, who has a sister affected with cancer of the bile duct but no family history of colorectal cancer (PMID: 26437257). This variant also has been detected in an individual affected with breast cancer (PMID: 26976419). This variant has not been identified 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 28, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3974_3976delAGA variant (also known as p.K1325del) is located in coding exon 9 of the MSH6 gene. This variant results from an in-frame AGA deletion at nucleotide positions 3974 to 3976. This results in the in-frame deletion of a lysine at codon 1325. This alteration has been reported in a homozygous state in an individual diagnosed with colorectal cancer at age 41 and lung cancer at age 44. This individual's family history is also significant for consanguineous parents and a sister who died of cholangiocarcinoma at 44 years old. Authors also question the relevance and penetrance of this alteration as no other cases of colorectal cancers had been described for this family (Carneiro da Silva F et al. PLoS ONE. 2015 Oct;10:e0139753). This alteration has also been reported in one family from a cohort of Latin American families suspected of Lynch syndrome (Rossi BM et al. BMC Cancer 2017 Sep;17(1):623), and in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome Uncertain:2
Sep 11, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant causes the in-frame deletion of lysine 1325 in the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a homozygous carrier affected with colorectal and lung cancer, who has a sister affected with cancer of the bile duct and has no family history of colorectal cancer (PMID: 26437257). This variant also has been detected in an individual affected with breast cancer (PMID: 26976419). This variant has not been identified 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. -

Jan 30, 2019
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

not provided Uncertain:2
Jan 30, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In-frame deletion of one amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in the homozygous state in an individual with consanguineous parents and colorectal cancer, whose personal history was not suggestive of constitutional mismatch repair deficiency (CMMR-D) and family history was not suggestive of Lynch syndrome (Carneiro da Silva et al., 2015); Located in the critical ATPase domain and MSH2 binding site (Kariola et al., 2002; Warren et al., 2007; Kansikas et al., 2011); This variant is associated with the following publications: (PMID: 27300758, 28874130, 26648449, 17531815, 21120944, 12019211, 26976419, 26437257) -

Feb 01, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Jan 17, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MSH6 c.3974_3976delAGA (p.Lys1325del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 247744 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3974_3976delAGA has been reported in the literature as a homozygous variant in a patient with colorectal cancer (CRC) who fulfilled the Bethesda guidelines, reporting consanguineous family, no family history of CRC and no associated features of CMMRD (Carneiro_2015, Rossi_2017), a patient with suspected Lynch syndrome (LS), MSI-High tumor, tumor with LOH for MSH2, first degree relatives with Lynch syndrome associated tumors (Jansen_2016), and a patient with breast cancer undergoing multigene cancer panel testing (Tung_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Carcinoma of colon Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MSH6 p.Lys1325del variant was identified in 2 of 1208 proband chromosomes (frequency: 0.002) from Brazilian and American individuals or families with suspected Lynch syndrome or breast cancer (Carneiro da Silva_2015_26437257, Tung_2016_26976419). One proband with suspected Lynch Syndrome was homozygous for the variant (parents had a consanguineous marriage), developed CRC at 41 years and had a sister diagnosed with colangiocarcinoma (Carneiro da Silva_2015_26437257). The variant was also identified in dbSNP (ID: rs587779300) “With Uncertain significance allele”, ClinVar (classified as uncertain significance, reviewed by an expert panel (2013); submitters: InSIGHT, Ambry Genetics, Counsyl, Invitae, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (4x), Cosmic (1x in a carcinoma of the female genital tract), Insight Colon Cancer Gene Variant Database (1x as Class 3), Zhejiang Colon Cancer Database, and Insight Hereditary Tumors Database (1x); and was not identified in GeneInsight-COGR, MutDB, UMD-LSDB, Mismatch Repair Genes Variant Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a lysine (lys) residue at codon 1325; the impact of this alteration on MSH6 protein function is not known. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

MSH6-related disorder Uncertain:1
Sep 11, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MSH6 c.3974_3976delAGA variant is predicted to result in an in-frame deletion (p.Lys1325del). This variant has been reported in the homozygous state in an individual who developed colon cancer (Carneiro da Silva et al. 2015. PubMed ID: 26437257). This variant has also been reported in a family and an unrelated individual with suspected Lynch syndrome (Rossi et al. 2017. PubMed ID: 28874130; Jansen et al. 2016. PubMed ID: 27300758) and in an individual with breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/89494). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Dec 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.3974_3976del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys1325del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast, ovarian, endometrial, and/or colorectal cancer (PMID: 26437257, 26648449, 26976419). ClinVar contains an entry for this variant (Variation ID: 89494). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Endometrial carcinoma Uncertain:1
Mar 14, 2024
Baylor Genetics
Significance: Uncertain significance
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

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587779300; hg19: chr2-48033759; API