rs386134250

chr11-64810109-T-Achr11-64810109-T-Cchr11-64810109-T-G

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>T(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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEN1 NM_001370259.2 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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-A is Pathogenic according to our data. Variant chr11-64810109-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 428034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1005854 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 484424

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 31, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2021	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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

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	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	24
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	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.88	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	0.82
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;.;.
Polyphen		0.65, 0.70	.;P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.69
MutPred		0.73		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
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		0.63
gMVP		0.52

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;