11-64810109-T-C

Variant names:

• chr11-64810109-T-C
• rs386134250
• NM_001370259.2:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000199 in 1,005,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000020 (0 hom.)
• Consequence: MEN1 NM_001370259.2 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.25
• Publications: 16 publications found

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

ACMG classification

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-C is Pathogenic according to our data. Variant chr11-64810109-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 36525.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	c.1A>G	p.Met1?	start_lost	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	c.1A>G	p.Met1?	start_lost	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000199 AC: 2 AN: 1005856 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 484426

African (AFR) AF: 0.00 AC: 0 AN: 23132

American (AMR) AF: 0.00 AC: 0 AN: 28094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13112

East Asian (EAS) AF: 0.00 AC: 0 AN: 13832

South Asian (SAS) AF: 0.00 AC: 0 AN: 47692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3148

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 829654

Other (OTH) AF: 0.00 AC: 0 AN: 34592

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:5 Other:1

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the translation initiation codon of the MEN1 protein. The next in-frame methionine is at codon 228, which if used for translation initiation would truncate the N-terminal domain containing binding sites to lens epithelium-derived growth factor (LEDGF) and MLL1 (PMID: 22327296), therefore the loss of p.Met1 is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. The loss of the translation initiation codon has been reported in multiple individuals and families affected with multiple endocrine neoplasia, type 1 (PMID: 15714081, 26515642, 26767918, 28736585, 29036195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Aug 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the translation initiation codon of the MEN1 protein. The next in-frame methionine is at codon 228, which if used for translation initiation would truncate the N-terminal domain containing binding sites to lens epithelium-derived growth factor (LEDGF) and MLL1 (PMID: 22327296), therefore the loss of p.Met1 is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. The loss of the translation initiation codon has been reported in multiple individuals and families affected with multiple endocrine neoplasia, type 1 (PMID: 15714081, 26515642, 26767918, 28736585, 29036195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Feb 17, 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: 36525). For these reasons, this variant has been classified as Pathogenic.

Oct 22, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 06-15-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Aug 18, 2011

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

not provided Pathogenic:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 08, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1 A>G variant in the MEN1 gene has previously been reported in at least one individual undergoing genetic testing for multiple endocrine neoplasia type 1 (Klein et al., 2005). This variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. Based on currently available evidence, we consider c.1A>G to be a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded."

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Pathogenic:1

Dec 13, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 11, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the MEN1 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This pathogenic mutation has been reported in a family with familial isolated hyperparathyroidism. Note: In this paper the M1? (c.1A>G) pathogenic mutation was incorrectly referred to as L112V; however HGMD and the authors of this paper have verified that this represents the same mutation (Villablanca A et al. Eur. J. Endocrinol. 2002 Sep; 147(3):313-22). This pathogenic mutation has also been reported in another affected family; however, specific clinical information was not provided (Klein RD et al. Genet. Med. 2005 Feb; 7(2):131-8).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 variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;.;.;.;T;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
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	0.84
Sift	Benign	0.040	D;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Vest4		0.87
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.50
gMVP		0.64
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386134250; hg19: chr11-64577581;