Genetic Variant MEN1:p.Glu26Gln (chr11-64810034-C-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_001370259.2(MEN1):c.76G>C(p.Glu26Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E26K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.13

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 31 uncertain in NM_001370259.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-64810034-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2 link	c.76G>C	p.Glu26Gln	missense_variant	Exon 2 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.76G>C	p.Glu26Gln	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Uncertain

0.48

T;.;.;.;.;D;D;D;D;T;.;T;.;.

Eigen

Benign

0.0065

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.89

.;L;L;L;L;L;L;L;L;.;.;.;.;.

PhyloP100

7.1

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.24

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

REVEL

Pathogenic

0.66

Sift

Benign

0.49

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

Sift4G

Benign

0.83

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

Polyphen

1.0, 0.10, 0.13

.;D;B;B;B;B;B;B;B;.;.;.;.;.

Vest4

0.55

MutPred

0.60

Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);Loss of disorder (P = 0.1371);

MVP

0.88

MPC

1.2

ClinPred

0.62

GERP RS

4.9

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.53

gMVP

0.69

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over