rs202066386

chr2-47806315-T-Achr2-47806315-T-Cchr2-47806315-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM5 PP3 BP4_Moderate BP6

The NM_000179.3(MSH6):c.3758T>A(p.Val1253Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,156 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. V1253A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:3
• Conservation: PhyloP100: 7.62

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47806313-AGT-AA is described in Lovd as [Pathogenic].
• PP3: Multiple lines of computational evidence support a deleterious effect 5: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.17562485).
• BP6: Variant 2-47806315-T-A is Benign according to our data. Variant chr2-47806315-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127591.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.3758T>A	p.Val1253Glu	missense_variant	8/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.3758T>A	p.Val1253Glu	missense_variant	8/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152224 Hom.: 0 Cov.: 33

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251190 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000711 AC: 104 AN: 1461814 Hom.: 0 Cov.: 33 AF XY: 0.0000756 AC XY: 55 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74502

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: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000609 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This missense variant replaces valine with glutamic acid at codon 1253 of the MSH6 protein. Computational prediction tool 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-associated cancer and/or polyps (PMID: 25142776, 25980754) and other non-Lynch or unspecified cancers (PMID: 26689913, 29684080, 31921681, 31391288), and in an unaffected individual (PMID: 31422574). This variant has also been identified in 42/282588 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 18, 2022	The p.V1253E variant (also known as c.3758T>A), located in coding exon 8 of the MSH6 gene, results from a T to A substitution at nucleotide position 3758. The valine at codon 1253 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration has been reported in multiple cohorts of patients undergoing multigene panel testing, including individuals diagnosed with a Lynch syndrome-associated cancer and/or polyps (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Yehia L et al. PLoS Genet. 2018 04;14:e1007352; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20; Young EL et al. BMC Cancer. 2018 Jun;18:697). It was identified in a 70-year-old individual with microsatellite-stable, mismatch repair protein-proficient colorectal cancer (Kraus C et al. Int. J. Cancer. 2015 Mar;136:E559-68), as well as two patients, one with breast and the other with renal cancer, from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec;6:10086). Additionally, this alteration was identified in 1/2515 controls and 0/165 individuals with colorectal cancer and/or polyps (Rosenthal EA et al. Hum. Genet. 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2023	Variant summary: MSH6 c.3758T>A (p.Val1253Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251190 control chromosomes, predominantly at a frequency of 0.00023 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.62 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3758T>A has been reported in the literature in individuals affected with or being tested for Lynch Syndrome, as well as in patients with breast or ovarian cancer (e.g. Kraus_2015, Lu_2015, Young_2018, Yurgelun_2015, Tsaousis_2019, Morak_2019, Li_2020, Kraemer_2019, Oliver_2019, Dorling_2021, Pereira_2022). However, the variant was also identified in many healthy controls (e.g., Dorling_2021, Rosenthal_2018). These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One publication reports experimental evidence evaluating an impact on RNA splicing and found that the variant had no effect (e.g., Frederiksen_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31422574, 25142776, 31391288, 26689913, 31332305, 31921681, 23621914, 31159747, 29945567, 25980754, 34445333, 35980532, 29684080, 30267214, 33471991). Ten ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: VUS (n = 8) and likely benign (n = 2). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 26, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with CRC. MaxMAF is 0.09%. Classified as DM? in HGMD. Classified in ClinVar as VUS by Invitae, Ambry, GeneDx (2 stars). MAF is greater than or equal to disease prevalence -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MSH6: PS3:Supporting, BP1, BS1:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28166811, 22949387, 23621914, 25142776, doi:10.5923/j.bioinformatics.20160602.03, 29684080, 25980754, 29945567, 31159747, 26689913, 31422574, 31391288, 31332305, 17531815, 21120944, 31921681, 30267214, 35980532, 36461907, 34445333, 33471991, Giacomazzi2022[preprint]) -

Lynch syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 12, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces valine with glutamic acid at codon 1253 of the MSH6 protein. Computational prediction tool 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-associated cancer and/or polyps (PMID: 25142776, 25980754) and other non-Lynch or unspecified cancers (PMID: 26689913, 29684080, 31921681, 31391288), and in an unaffected individual (PMID: 31422574). This variant has also been identified in 42/282588 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. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH6 p.Val1253Glu variant was identified in 1 of 304 proband chromosomes (frequency: 0.003) from individuals or families with colorectal cancer (Kraus 2014). The variant was also identified in dbSNP (ID: rs202066386) as "With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, and three other submitters), and in UMD-LSDB. The variant was identified in control databases in 41 of 276934 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 5 of 6460 chromosomes (freq: 0.0008), Latino in 1 of 34382 chromosomes (freq: 0.00002), European in 25 of 126474 chromosomes (freq: 0.0002), Finnish in 10 of 25788 chromosomes (freq: 0.0004); it was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. An experimental study on predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein identified the p.Val1253Glu has an impact on MSH6 (Terui 2013). The p.Val1253 residue is conserved across mammals and other organisms, and 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

Endometrial carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 11, 2023

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.33	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	1.0	D;D;D;D
Sift4G	Benign	0.11	T
Vest4		0.51
MVP		0.94
ClinPred		0.54	D
GERP RS		5.5

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: rs202066386; hg19: chr2-48033454;