rs786202889

chr2-47803474-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3 PP5

The NM_000179.3(MSH6):c.3227G>A(p.Arg1076His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1076C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 9.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47803473-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89357.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798
• PP5: Variant 2-47803474-G-A is Pathogenic according to our data. Variant chr2-47803474-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186361.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3227G>A	p.Arg1076His	missense_variant	5/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3227G>A	p.Arg1076His	missense_variant	5/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251346 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135850

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 08, 2023	The p.R1076H variant (also known as c.3227G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3227. The arginine at codon 1076 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals whose Lynch syndrome-associated tumors displayed isolated loss of MSH6 on immunohistochemistry (IHC) and/or had high microsatellite instability (MSI-H) (Ambry internal data). This alteration was reported in one family from a cohort of 59 Asian families meeting Amsterdam I or Amsterdam II criteria (Liu Y et al. PLoS ONE. 2014 Apr;9:e94170). This alteration has also been reported in multiple patients with a personal/family history of breast and/or ovarian cancer and patients with pancreatic cancer (Wong ESY et al. NPJ Genom. Med. 2016 Jan 13;1:15003; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg. 2020 11;231:527-535.e14). Another alteration at the same amino acid position, p.R1076C, has been reported as likely pathogenic due to its identification in individuals with clinical features of hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and constitutional mismatch repair deficiency (CMMRD) syndrome (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Okkels H et al. Int J Colorectal Dis. 2006 Dec;21:847-50; Rahner N et al. Am. J. Med. Genet. A. 2008 May;146A:1314-9; Schofield L et al. Int. J .Cancer. 2009 Sep;125:1492-3; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7; Gardès P et al. J. Immunol. 2012 Feb;188:2023-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2023	This missense variant replaces arginine with histidine at codon 1076 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with Lynch syndrome, pancreatic, colorectal, and breast and/or ovarian cancers (PMID: 24710284, 26898890, 27153395, 29263802, 28767289, 37088804; ClinVar: SCV000216699.6). Different variants occurring at the same codon, c.3226C>T (p.Arg1076Cys) and c.3226C>G (p.Arg1076Gly), are well-documented pathogenic mutations (ClinVar Variation ID: 89357, 428337). This variant has been identified in 2/251346 chromosomes 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 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2017	Variant summary: The MSH6 c.3227G>A (p.Arg1076His) variant located in the DNA mismatch repair MutS, core domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/121322 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). Multiple publications have cited the variant in affected individuals, observed as both germline and assumed somatic occurrences, however, co-occurrence and cosegregation data was very limited. Therefore, establishing a pathogenic or benign impact for this variant cannot be obtained with this information. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie additional clinical studies and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1076 of the MSH6 protein (p.Arg1076His). This variant is present in population databases (rs779617676, gnomAD 0.002%). This missense change has been observed in individuals with Lynch syndrome and/or MSH6-related conditions (PMID: 24710284, 26898890, 31997046; external communication). ClinVar contains an entry for this variant (Variation ID: 186361). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. This variant disrupts the p.Arg1076 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15483016, 16418736, 16525781, 18409202, 18566915, 21039432; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 15, 2023

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

May 01, 2018

MSH6 NM_000179.2:c.3227G>A has a 58.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.21	T;D;T;D;T
Polyphen		1.0	.;.;.;D;.
Vest4		0.84
MutPred		0.85		.;.;.;Loss of sheet (P = 0.0817);.;
MVP		0.93
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.46
gMVP		0.92

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

Other links and lift over

dbSNP: rs779617676; hg19: chr2-48030613; COSMIC: COSV52274821; COSMIC: COSV52274821;