11-64806312-G-C

Variant names:

• chr11-64806312-G-C
• rs750904332
• NM_001370259.2:c.969C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.969C>G​(p.Tyr323*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y323Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.78
• Publications: 5 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64806312-G-C is Pathogenic according to our data. Variant chr11-64806312-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 449058.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.969C>G	p.Tyr323*	stop_gained	Exon 7 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.984C>G	p.Tyr328*	stop_gained	Exon 7 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.969C>G	p.Tyr323*	stop_gained	Exon 7 of 11	NP_001357180.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.969C>G	p.Tyr323*	stop_gained	Exon 7 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.969C>G	p.Tyr323*	stop_gained	Exon 7 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.969C>G	p.Tyr323*	stop_gained	Exon 8 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Jun 29, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr323*) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with multiple endocrine neoplasia type 1 (PMID: 9215689). ClinVar contains an entry for this variant (Variation ID: 449058). A different variant (c.969C>A) giving rise to the same protein effect observed here (p.Tyr323*) has been reported in individuals affected with multiple endocrine neoplasia (PMID: 12791038, 22026581, 25309785). Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334).

not provided Pathogenic:1

May 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.984C>G; p.(Y328*); This variant is associated with the following publications: (PMID: 25525159, 9215689, 9540988, 12791038, 15464422, 12807514)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		1.8
Vest4		0.96
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs750904332; hg19: chr11-64573784;