11-64808033-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_001370259.2(MEN1):c.512G>A(p.Arg171Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,078 control chromosomes in the GnomAD database, including 313 homozygotes. 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. R171W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 14 hom., cov: 32)

Exomes 𝑓: 0.018 ( 299 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:27O:2

Conservation

PhyloP100: 2.73

Publications

49 publications found

Variant links:

Genes affected

MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]

MEN1 Gene-Disease associations (from GenCC):

multiple endocrine neoplasia type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
familial isolated hyperparathyroidism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pituitary gigantism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

MEN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 28 uncertain in NM_001370259.2

PP2

Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.

BP4

Computational evidence support a benign effect (MetaRNN=0.014003247).

BP6

Variant 11-64808033-C-T is Benign according to our data. Variant chr11-64808033-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41854.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1935/152278) while in subpopulation NFE AF = 0.0213 (1447/68028). AF 95% confidence interval is 0.0204. There are 14 homozygotes in GnomAd4. There are 924 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1935 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2 link	c.512G>A	p.Arg171Gln	missense_variant	Exon 3 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7 link	c.512G>A	p.Arg171Gln	missense_variant	Exon 3 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1935

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00878

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0213

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.0120

AC:

3017

AN:

250912

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00456

Gnomad AMR exome

AF:

0.00773

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.00724

Gnomad FIN exome

AF:

0.00616

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0181

AC:

26503

AN:

1461800

Hom.:

299

Cov.:

AF XY:

0.0174

AC XY:

12671

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00326

AC:

109

AN:

33480

American (AMR)

AF:

0.00776

AC:

347

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00471

AC:

123

AN:

26136

East Asian (EAS)

AF:

0.00421

AC:

167

AN:

39690

South Asian (SAS)

AF:

0.00160

AC:

138

AN:

86252

European-Finnish (FIN)

AF:

0.00605

AC:

323

AN:

53380

Middle Eastern (MID)

AF:

0.00711

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0219

AC:

24399

AN:

1111986

Other (OTH)

AF:

0.0142

AC:

856

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1595

3189

4784

6378

7973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

920

1840

2760

3680

4600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0127

AC:

1935

AN:

152278

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

924

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00436

AC:

181

AN:

41546

American (AMR)

AF:

0.00877

AC:

134

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.00502

AC:

AN:

5182

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0213

AC:

1447

AN:

68028

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0170

Hom.:

Bravo

AF:

0.0121

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0209

AC:

180

ExAC

AF:

0.0118

AC:

1427

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0182

EpiControl

AF:

0.0198

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:27Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Uncertain:1Benign:8Other:1

Oct 06, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mar 11, 2015

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpretted as Likely benign and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2023

Myriad Genetics, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not specified

Benign:7Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jun 05, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MEN1: BS1, BS2 -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22995991, 20981092, 21521296, 22703879, 24997771, 21819486, 24728327, 18221402, 27153395, 30324798, 30869828) -

Hereditary cancer-predisposing syndrome

Benign:3

Feb 24, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jun 19, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2016

Vantari Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple endocrine neoplasia

Benign:1

May 05, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyperparathyroidism

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;.;.;D;D;D;D;D;.;D

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.95

D;D;.;.;D;.;.;D;.;D;D;D

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

0.69

.;.;.;.;.;N;N;N;N;.;.;.

PhyloP100

2.7

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.75

N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.10

T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.15

T;T;T;T;T;T;T;T;T;.;T;T

Polyphen

0.76, 0.99, 0.99

.;P;D;D;D;D;D;D;D;.;.;.

Vest4

0.20

MPC

1.2

ClinPred

0.017

GERP RS

4.8

PromoterAI

0.039

Neutral

(source)

Varity_R

0.34

gMVP

0.78

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over