11-64807010-C-T

Position:

• chr11-64807010-C-T

Variant summary

Our verdict is Pathogenic. Variant got 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:5
• Conservation: PhyloP100: 6.41

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 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 ClinVar 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 Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.912+1G>A		splice_donor_variant, intron_variant		ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.912+1G>A		splice_donor_variant, intron_variant		5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 96254). Disruption of this splice site has been observed in individuals with clinical features of multiple endocrine neoplasia type 1 (PMID: 10090472, 18753104). This variant is not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2016	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2022

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
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

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