11-64810109-T-C

Variant summary

Our verdict is Pathogenic. Variant got 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:9 O:1
• Conservation: PhyloP100: 4.25

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001370259.2 (MEN1) was described as [Likely_pathogenic] in ClinVar as 188376
• 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 [Likely_pathogenic]. Clinvar id is 36525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64810109-T-C is described in Lovd as [Pathogenic]. Variant chr11-64810109-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-64810109-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.1A>G	p.Met1?	start_lost	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1A>G	p.Met1?	start_lost	2/10	5	NM_001370259.2	P3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000241

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2017	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." -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 13, 2016

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2017

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. 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). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, 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	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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
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;.;.
Polyphen		0.81, 0.84	.;P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.87
MutPred		0.84		Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);Loss of catalytic residue at M1 (P = 0.0706);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.50
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs386134250; hg19: chr11-64577581;