rs786204242

Variant names:

• chr11-64810107-C-T
• rs786204242
• NM_001370259.2:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1 PS1_Moderate PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000219119: Disruption of the initiator codon has been observed in individuals with multiple endocrine neoplasia type 1 (PMID:28736585, 29036195" and additional evidence is available in ClinVar.

• 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
• Publications: 1 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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 24 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 258 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
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000219119: Disruption of the initiator codon has been observed in individuals with multiple endocrine neoplasia type 1 (PMID: 28736585, 29036195; internal data).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 188376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370259.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.3G>A	p.Met1?	start_lost	Exon 2 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.3G>A	p.Met1?	start_lost	Exon 2 of 11	NP_001357180.2	A0A5F9ZHS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 2 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 2 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 3 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

Alfa AF: 0.00000539 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Multiple endocrine neoplasia, type 1 (5)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.1
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.88
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.83
MutPred		0.77		Gain of methylation at K4 (P = 0.0458)
MVP		0.99
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.58
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204242; hg19: chr11-64577579; COSMIC: COSV107320164; COSMIC: COSV107320164;