rs786204242

Positions:

• chr11-64810107-C-T

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.3G>A​(p.Met1?) variant causes a start lost 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: 30)
• Consequence: MEN1 NM_001370259.2 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.09

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 [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64810107-C-T is Pathogenic according to our data. Variant chr11-64810107-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.3G>A	p.Met1?	start_lost	2/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.3G>A	p.Met1?	start_lost	2/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 25, 2021	The c.3G>A, p.Met1? variant identified in the MEN1 gene has been reported previously in individuals affected with MEN1-related disease (PMID:26767918). This variant affects the initiator methionine of the MEN1 mRNA, and the next in-frame methionine is located at codon 228. The variant is absent in the gnomAD v3.1.1 database, indicating it is an extremely rare allele in the populations represented in this database. Other variants that disrupt the initiator methionine in MEN1 also have been observed in affected individuals with MEN1-related disease (PMID: 28736585, 29036195, 15714081, 26515642). Based on the available evidence, the heterozygous start lost variant c.3G>A, p.Met1? in the MEN1 gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 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 MEN1-related disease (PMID: 15714081, 26515642, 28736585, 29036195; Invitae). ClinVar contains an entry for this variant (Variation ID: 188376). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 03, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28736585, 35407574, 29036195, 31482957, 36654999, 28329921, 24915123]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2020

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26767918) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2016

The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the MEN1 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. 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	0.62	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.;.;.;T;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.94	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	-1.4	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen		0.91, 0.93	.;P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.83
MutPred		0.77		Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);Gain of methylation at K4 (P = 0.0458);
MVP		0.99
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs786204242; hg19: chr11-64577579;