rs587779205

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MSH6
NM_000179.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 4.66

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]

MSH6 links:

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 links:

MSH6 (HGNC:):

MSH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1846863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3 linkuse as main transcript	c.1133G>A	p.Arg378Lys	missense_variant	4/10	ENST00000234420.11	NP_000170.1	P52701-1Q3SWU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11 linkuse as main transcript	c.1133G>A	p.Arg378Lys	missense_variant	4/10	1	NM_000179.3	ENSP00000234420.5		P52701-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250942

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135594

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

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:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2023	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 27, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 10, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 01, 2024

- -

Carcinoma of colon

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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 (Jâˆšâ‰¥ri 2015). The variant was also identified in dbSNP (ID: rs587779205) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹ ,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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.016

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Uncertain

0.44

.;.;T;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.056

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

.;T;T;T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.0

.;.;M;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.98

.;N;N;.;N

REVEL

Uncertain

0.35

Sift

Benign

1.0

.;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0090

.;.;B;.;.

Vest4

0.24

MutPred

0.31

.;.;Gain of ubiquitination at R378 (P = 0.0101);.;.;

MVP

0.90

ClinPred

0.50

GERP RS

4.3

Varity_R

0.46

gMVP

0.59

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over