rs386134250

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_001370259.2(MEN1):c.1A>T(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MEN1
NM_001370259.2 initiator_codon

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.25

Publications

16 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: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 256 pathogenic variants. Next in-frame start position is after 228 codons. Genomic position: 64807653. Lost 0.372 part of the original CDS.

PS1

Another start lost variant in NM_001370259.2 (MEN1) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-64810109-T-A is Pathogenic according to our data. Variant chr11-64810109-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2 link	c.1A>T	p.Met1?	initiator_codon_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.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1005854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

484424

African (AFR)

AF:

0.00

AC:

AN:

23132

American (AMR)

AF:

0.00

AC:

AN:

28094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13112

East Asian (EAS)

AF:

0.00

AC:

AN:

13832

South Asian (SAS)

AF:

0.00

AC:

AN:

47692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829652

Other (OTH)

AF:

0.00

AC:

AN:

34592

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Pathogenic:3

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the MEN1 mRNA. The next in-frame methionine is located at codon 228. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 28736585, 29036195; Invitae). ClinVar contains an entry for this variant (Variation ID: 428034). For these reasons, this variant has been classified as Pathogenic.

May 23, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MEN1 c.1A>T (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Other start loss variants such as c.3G>A, c.2T>A and c.1A>G all translating to the same effect, namely p.M1? have been reported in association with Multiple Endocrine Neoplasia Type 1 supporting the essential impact of this variant to loss of function. The variant was absent in 160466 control chromosomes. Although this variant has been included in mutational updates reporting germline MEN1 variants and included in the UMD-MEN1 database (example, Concolino_2016, Romanet_2019), to our knowledge, no case level reports of the occurrence of c.1A>T in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Dec 31, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MEN1 c.1A>T; p.Met1? variant is reported in the literature in at least one individual affected with multiple endocrine neoplasia, type 1 (Concolino 2016). This variant is reported in ClinVar (Variation ID: 428034), and is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant affects the initiation codon and is predicted to affect the protein translation start site. Additionally, other variants affecting the initiation codon (c.1A>G, p.Met1?; c.2T>A, p.Met1?) have been reported in individuals with multiple endocrine neoplasia, type 1 and are considered pathogenic (Kaiwar 2017, Klein 2005, Pardi 2017, Remde 2015). Based on available information, the c.1A>T; p.Met1? variant is considered to be pathogenic. References: Concolino P et al. Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. Cancer Genet. 2016 Jan-Feb;209(1-2):36-41. Kaiwar C et al. Late onset asymptomatic pancreatic neuroendocrine tumor - A case report on the phenotypic expansion for MEN1. Hered Cancer Clin Pract. 2017 Jul 21;15:10. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. Pardi E et al. Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. PLoS One. 2017 Oct 16;12(10):e0186485. Remde H et al. A patient with novel mutations causing MEN1 and hereditary multiple osteochondroma. Endocrinol Diabetes Metab Case Rep. 2015;2015. pii: 14-0120.

not provided

Pathogenic:1

Nov 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MEN1 c.1A>T variant disrupts the translation initiation codon of the MEN1 mRNA and is predicted to interfere with MEN1 protein synthesis. This variant has not been reported in the published literature in individuals with MEN1 syndrome in the published literature. However, a different variant that occurs at the same position (MEN1 c.1A>G) has been reported in individuals with MEN1 syndrome (PMID: 26767918 (2015), 29036195 (2017))). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 07, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the MEN1 gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation has been reported in several individuals meeting clinical diagnostic criteria for multiple endocrine neoplasia type 1 (MEN1) (Ventura M et al. Arch Endocrinol Metab, 2019 Sep;63:516-523; Romanet P et al. J Clin Endocrinol Metab, 2019 03;104:753-764; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.32

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

4.3

PROVEAN

Benign

-1.1

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

REVEL

Pathogenic

0.82

Sift

Uncertain

0.024

D;D;D;D;D;D;D;D;D;D;T;T;T;T

Sift4G

Pathogenic

0.0

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

Vest4

0.69

ClinPred

0.99

GERP RS

4.2

PromoterAI

-0.34

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.63

gMVP

0.52

Mutation Taster

=0/200

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over