chr11-64804645-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_001370259.2(MEN1):​c.1522C>A​(p.Gln508Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000145 in 1,449,898 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q508E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 missense

Scores

3
4
12

Clinical Significance

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

Conservation

PhyloP100: 4.98

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

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.
BP6
Variant 11-64804645-G-T is Benign according to our data. Variant chr11-64804645-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403081.
BS2
High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MEN1NM_001370259.2 linkc.1522C>A p.Gln508Lys missense_variant Exon 10 of 10 ENST00000450708.7 NP_001357188.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MEN1ENST00000450708.7 linkc.1522C>A p.Gln508Lys missense_variant Exon 10 of 10 5 NM_001370259.2 ENSP00000394933.3 O00255-2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD2 exomes
AF:
0.0000176
AC:
4
AN:
227726
AF XY:
0.0000160
show subpopulations
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000295
Gnomad OTH exome
AF:
0.000176
GnomAD4 exome
AF:
0.0000145
AC:
21
AN:
1449898
Hom.:
0
Cov.:
43
AF XY:
0.00000971
AC XY:
7
AN XY:
720992
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33236
American (AMR)
AF:
0.00
AC:
0
AN:
43818
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25942
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39462
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85874
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47354
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5558
European-Non Finnish (NFE)
AF:
0.0000171
AC:
19
AN:
1108666
Other (OTH)
AF:
0.0000333
AC:
2
AN:
59988
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
34
Alfa
AF:
0.0000567
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.00000830
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1Benign:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 06, 2024
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: Reported in 1 proband; ExAC: 1/51192 European chromosomes -

Hereditary cancer-predisposing syndrome Benign:1
Nov 15, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
15
DANN
Benign
0.73
DEOGEN2
Benign
0.24
T;.;.;.;.;T;T;T;T
Eigen
Benign
-0.94
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.79
T;T;.;.;T;.;.;T;.
M_CAP
Pathogenic
0.85
D
MetaRNN
Uncertain
0.61
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Benign
0.69
.;.;.;.;.;N;N;N;N
PhyloP100
5.0
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.43
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.55
Sift
Benign
0.75
T;T;T;T;T;T;T;T;T
Sift4G
Benign
0.77
T;T;T;T;T;T;T;T;T
Polyphen
0.0040, 0.0050
.;B;B;B;B;B;B;B;B
Vest4
0.36
MutPred
0.77
.;.;.;.;.;Gain of glycosylation at Q513 (P = 0.0095);Gain of glycosylation at Q513 (P = 0.0095);Gain of glycosylation at Q513 (P = 0.0095);Gain of glycosylation at Q513 (P = 0.0095);
MVP
1.0
MPC
2.3
ClinPred
0.052
T
GERP RS
4.1
Varity_R
0.22
gMVP
0.71
Mutation Taster
=0/100
disease causing

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

Other links and lift over

dbSNP: rs386833403; hg19: chr11-64572117; API