rs150990541

chr2-47806474-G-Achr2-47806474-G-Cchr2-47806474-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_000179.3(MSH6):c.3824G>A(p.Cys1275Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000756 in 1,613,954 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C1275F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 6.91

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 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, 17 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.339109).
• BP6: Variant 2-47806474-G-A is Benign according to our data. Variant chr2-47806474-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127594.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3824G>A	p.Cys1275Tyr	missense_variant	9/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3824G>A	p.Cys1275Tyr	missense_variant	9/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152138 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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250998 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135716

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: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461816 Hom.: 0 Cov.: 35 AF XY: 0.0000756 AC XY: 55 AN XY: 727214

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74314

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000603 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and glioma (Lu et al., 2015; Tung et al., 2015); This variant is associated with the following publications: (PMID: 23621914, 25186627, 17531815, 21120944, 26689913) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	- -

Lynch syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MSH6 p.Cys1275Tyr variant was identified in 1 of 4316 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Tung 2015). The variant was also identified in dbSNP (ID: rs150990541) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, and three other submitters), Cosmic (1x in Large intestine tissue), and MutDB. The variant was not identified in GeneInsight-COGR, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 9 of 276850 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 9 of 126428 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Cys1275 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces cysteine with tyrosine at codon 1275 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 observed in one individual each affected with breast cancer (PMID: 25186627) and low-grade glioma (PMID: 26689913). This variant has been identified in 8/282376 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 29, 2024	The p.C1275Y variant (also known as c.3824G>A), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 3824. The cysteine at codon 1275 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	This missense variant replaces cysteine with tyrosine at codon 1275 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 observed in one individual each affected with breast cancer (PMID: 25186627) and low-grade glioma (PMID: 26689913). This variant has been identified in 8/282376 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. -

Lynch syndrome 5 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 05, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 01, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 03, 2019

Variant summary: MSH6 c.3824G>A (p.Cys1275Tyr) results in a non-conservative amino acid change located in the ATPase domain of DNA mismatch repair MUTS family domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250998 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3824G>A has been reported in the literature in individuals affected with cancer (Lu_2015, Tung_2014). These reports 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. Six ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	0.067	T;T;D;T;T
Polyphen		0.95	.;.;.;P;.
Vest4		0.54
MVP		0.90
ClinPred		0.42	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.70

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: rs150990541; hg19: chr2-48033613; COSMIC: COSV52277785; COSMIC: COSV52277785;