rs41557217

chr2-47798646-A-Cchr2-47798646-A-Gchr2-47798646-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000179.3(MSH6):c.663A>C(p.Glu221Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,612,862 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E221K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:17 O:1
• Conservation: PhyloP100: -0.266

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031133354).
• BP6: Variant 2-47798646-A-C is Benign according to our data. Variant chr2-47798646-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89552.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=4, not_provided=1, Uncertain_significance=3}. Variant chr2-47798646-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00063 (96/152354) while in subpopulation AMR AF= 0.000915 (14/15294). AF 95% confidence interval is 0.000716. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH6	NM_000179.3	c.663A>C	p.Glu221Asp	missense_variant	4/10	ENST00000234420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH6	ENST00000234420.11	c.663A>C	p.Glu221Asp	missense_variant	4/10	1	NM_000179.3	P4

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152236 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000706 AC: 176 AN: 249320 Hom.: 0 AF XY: 0.000801 AC XY: 108 AN XY: 134854

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000760 AC: 1110 AN: 1460508 Hom.: 0 Cov.: 34 AF XY: 0.000801 AC XY: 582 AN XY: 726568

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.0000576

Gnomad4 NFE exome AF: 0.000846

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152354 Hom.: 1 Cov.: 32 AF XY: 0.000711 AC XY: 53 AN XY: 74510

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000877 Hom.: 0

Bravo AF: 0.000646

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000618 AC: 75

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:17 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2016	Variant summary: The MSH6 c.663A>C (p.Glu221Asp) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 75/119664 (1/1595), which is approximately 4 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037 (0.0001421), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	This variant is associated with the following publications: (PMID: 27153395, 28767289, 17453009, 18269114, 24728327, 23621914, 26300997, 22290698, 21153778, 23047549, 26898890, 26333163, 17344846, 28531214, 28481244, 28874130, 29575718, 18301448, 31159747, 32854451) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MSH6: BP1, BP4, BP5 -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 28, 2022	- -

not specified Uncertain:1 Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 02, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 24, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Lynch syndrome 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 01, 2019	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. -

Abnormality of the ovary Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 16, 2021

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 17, 2023

- -

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.Glu221Asp variant was identified in 7 of 1567 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer (Devlin 2008, Steinke 2008, Bodian 2014, Liccardo 2017, Overbeek 2007, Simbolo 2015). The variant was also identified in dbSNP (ID: rs41557217) as "With Uncertain significance, other allele ", ClinVar (classified as benign by Invitae, Ambry Genetics and one clinical laboratory; as likely benign by GeneDx and four clinical laboratories; as uncertain significance by tree submitters), COGR, Cosmic (1x in Haematopoietic and lymphoid tissue), MutDB, UMD-LSDB (3x as unclassified variant), Mismatch Repair Genes Variant Database (1x), and in Insight Hereditary Tumors Database (2x VUS). The variant was not identified in Zhejiang University Database. The variant was identified in control databases in 189 of 275098 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 23956 chromosomes (freq: 0.0003), Other in 3 of 6442 chromosomes (freq: 0.0005), Latino in 12 of 34380 chromosomes (freq: 0.0003), European in 133 of 126092 chromosomes (freq: 0.001), East Asian in 1 of 18824 chromosomes (freq: 0.00005), Finnish in 1 of 24524 chromosomes (freq: 0.00004), and South Asian in 33 of 30752 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish population. The p.Glu221 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. In addition, in functional assay using oligonucleotide-directed mutagenesis screen the variant was not identified as MMR abrogating; the variant was found in patients who also harbored a second, known pathogenic mutation in one of the DNA MMR genes that was likely causative for the LS phenotype (Houlleberghs 2017). The p.Glu221Asp was also detected in a second patient who was 83 years old and did not have a family history suspicious for LS. The observation of this variant with a co-occurring pathogenic variant (MLH1, EXON05-8, c.381-?_677del+?) by our laboratory increases the likelihood this 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	9.7
Dann	Uncertain	0.98
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.031	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.87	N;N;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.16	T;T;.;T
Sift4G	Benign	0.42	T;T;T;D
Polyphen		0.0030	.;B;.;.
Vest4		0.17
MutPred		0.092		.;Gain of relative solvent accessibility (P = 0.09);.;.;
MVP		0.84
ClinPred		0.0068	T
GERP RS		-0.72
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.2
Varity_R		0.032
gMVP		0.073

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: rs41557217; hg19: chr2-48025785; COSMIC: COSV52286342; COSMIC: COSV52286342;