rs587779205

Variant names:

• chr2-47799116-G-A
• rs587779205
• NM_000179.3:c.1133G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47799116-G-A
• chr2-47799116-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000179.3(MSH6):​c.1133G>A​(p.Arg378Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 4.66
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 50 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.1846863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.1133G>A	p.Arg378Lys	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.1133G>A	p.Arg378Lys	missense_variant	Exon 4 of 10	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250942 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

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: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112000

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jul 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R378K variant (also known as c.1133G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1133. The arginine at codon 378 is replaced by lysine, an amino acid with highly similar properties. This variant has been reported in a Dutch Caucasian female with endometrioid endometrial cancer and ovarian cancer diagnosed at age 40, who also had a pathogenic MSH6 mutation, p.R482*. This individual's family history met Amsterdam II Criteria (Hendriks YM et al. Gastroenterology. 2004 Jul;127:17-25; Jóri B et al. Oncotarget. 2015 Dec;6:41108-22). This variant has been reported in an individual with tubo-ovarian cancer of mixed histology (Delahunty R et al. J Clin Oncol, 2022 Jun;40:2036-2047). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Jun 21, 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 lysine at codon 378 of the MSH6 protein. Computational prediction 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 reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 35263119), as well as in individuals affected with Lynch syndrome who also carried a truncating MSH6 variant, p.Arg482*, in cis that could explain the observed phenotype (PMID: 15236168, 26517685). This variant has been identified in 3/250942 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.

not specified Uncertain:1

Sep 27, 2022

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.1133G>A (p.Arg378Lys) results in a 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. One computational prediction method (PON-MMR2) also reports a benign outcome (Niroula_2015). The variant allele was found at a frequency of 1.2e-05 in 250942 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1133G>A has been reported in the literature in a deceased individual affected with Tubo-ovarian cancer without strong evidence for causality (Delahunty_2022). This report do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Co-occurrences with other pathogenic variants have been reported in the UMD database (MSH6 c.1444C>T, p.Arg482*), in an index case with adenocarcinoma in situ on a colon polyp at age 39 and his father affected with colorectal cancer. The mismatch repair function is reported to be MSI-high with IHC demonstrating MSH6 negative/MLH1+MSH2+PMS2+ staining pattern. These findings provide additional supporting evidence for a benign role attributed to this specific variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Lynch syndrome Uncertain:1

Jul 10, 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 lysine at codon 378 of the MSH6 protein. Computational prediction 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 reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 35263119), as well as in individuals affected with Lynch syndrome who also carried a truncating MSH6 variant, p.Arg482*, in cis that could explain the observed phenotype (PMID: 15236168, 26517685). This variant has been identified in 3/250942 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.

not provided Uncertain:1

May 14, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with early-onset endometrial cancer, who also carried a familial MSH6 nonsense variant (Jori 2015).; This variant is associated with the following publications: (PMID: 22290698, 26517685, 26333163, 15236168)

Endometrial carcinoma Uncertain:1

Mar 01, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Arg378Lys variant was identified in 1 of 70 proband chromosomes (frequency: 0.0142857142857143) from individuals or families with endometrial cancer and listed as class 3 variants (Jóri 2015). The variant was also identified in dbSNP (ID: rs587779205) as “With Uncertain significance allele” ,ClinVar (2x, as uncertain significance), Clinvitae (1x, as uncertain significance), UMD-LSDB (2 records , as uncertain significance, co-occurring with MSH6 pathogenic variant [c.1444T>C, p.Arg482X]), Insight Colon Cancer Gene Variant Database (3x, as class 3, ), Insight Hereditary Tumors Database (3x, with "function effect unknown"), databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database and Mismatch Repair Genes Variant databases. The variant was identified in control databases in 3 of 245686 chromosomes at a frequency of 0.000012 (Genome Aggregation Consortium Feb 27, 2017)". The p.Arg378 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A co-occurring pathogenic MSH6 variant (c.1444T>C, p.Arg482X) is identified in 1 individual with CRC in our laboratory, increasing the likelihood that p.Arg378Lys variant does not have clinical significance. 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.

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 02, 2024

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	0.13
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.0	.;.;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.056
LIST_S2	Benign	0.0	.;T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.0	.;.;M;.;.
PhyloP100		4.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.0	.;N;N;.;N
Sift	Pathogenic	0.0	.;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Vest4		0.24
ClinPred		0.50	D
GERP RS		4.3
Varity_R		0.46
gMVP		0.59
Mutation Taster		=55/45	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: rs587779205; hg19: chr2-48026255;