11-64807010-C-T

Variant names:

• chr11-64807010-C-T
• rs398124437
• NM_001370259.2:c.912+1G>A

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.912+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.41
• Publications: 6 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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64807010-C-T is Pathogenic according to our data. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807010-C-T is described in CliVar as Pathogenic. Clinvar id is 96254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.912+1G>A		splice_donor_variant, intron_variant	Intron 6 of 9	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.912+1G>A		splice_donor_variant, intron_variant	Intron 6 of 9	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.000644 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Apr 09, 2025

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18753104, 10090472]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18753104, 10090472, 34183184, 39112918]. -

Jul 19, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEN1 c.912+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. Experimental evidence supports these predictions demonstrating that this variant affects mRNA splicing, leading to deletion of exon 6 in the MEN1 transcript and resulting in a frameshift and a premature stop codon (Mutch_ 1999 and Alzahrani_2008). The variant was absent in 250826 control chromosomes (gnomAD). c.912+1G>A has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (examples: Mutch_ 1999 and Alzahrani_2008). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 6 of the MEN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 (PMID: 10090472, 18753104). ClinVar contains an entry for this variant (Variation ID: 96254). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Dec 11, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.912+1 G>A splice site variant in the MEN1 gene has been previously reported in association with multiple endocrine neoplasia type 1 (MEN1) (Mutch et al., 1999). This variant destroys the canonical splice donor site in intron 6, and is expected to cause abnormal gene splicing. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 12, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.912+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the MEN1 gene. This mutation was detected in an individual with a confirmed diagnosis of multiple endocrine neoplasia type 1 (Mutch MG, et al. Hum. Mutat. 1999;13(3):175-85). In addition, this mutation was detected in 16 year old female with Cushing syndrome attributable to a cortisol-producing adrenal adenoma, hyperparathyroidism, and pituitary microprolactionma. RNA studies confirmed that this mutation causes skipping of exon 6 in the MEN1 transcript, a shift in reading frame, and a premature stop codon 64 amino acids downstream (Alzahrani AS, et al. Endocr Pract;14(5):595-602). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the information presented in the literature, since mutations that disrupt the canonical splice donor site are typically deleterious in nature, 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	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.4
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398124437; hg19: chr11-64574482; COSMIC: COSV53643674;