NM_001370259.2:c.1350+1_1350+11delGTGAGGGACAG

Variant names:

• chr11-64805022-GCTGTCCCTCAC-G
• rs764570645
• NM_001370259.2:c.1350+1_1350+11delGTGAGGGACAG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1350+1_1350+11delGTGAGGGACAG variant causes a splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.62

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.090016365 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64805022-GCTGTCCCTCAC-G is Pathogenic according to our data. Variant chr11-64805022-GCTGTCCCTCAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 201001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805022-GCTGTCCCTCAC-G is described in Lovd as [Pathogenic]. Variant chr11-64805022-GCTGTCCCTCAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1350+1_1350+11delGTGAGGGACAG		splice_donor_variant, splice_region_variant, intron_variant	Intron 9 of 9	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1350+1_1350+11delGTGAGGGACAG		splice_donor_variant, splice_region_variant, intron_variant	Intron 9 of 9	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4

Jun 08, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a 11-basepair deletion in intron 9 of the MEN1 gene, abolishing the intron 9 splice donor site. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in multiple individuals affected with MEN1 and (primary hyperparathyroidism (PMID: 10090472, 16563611, 17065424, 27846313, 30324798). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MEN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Jun 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 9 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 multiple endocrine neoplasia, type 1 (PMID: 9709921, 10090472). ClinVar contains an entry for this variant (Variation ID: 201001). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 04, 2025

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.1350+1_1350+11del11 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of MEN1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 1613138 control chromosomes. c.1350+1_1350+11del11 has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (Mutch_1999, Jager_2006, Kong_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30324798, 16563611, 27846313, 10090472, 9709921). ClinVar contains an entry for this variant (Variation ID: 201001). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a 11-basepair deletion in intron 9 of the MEN1 gene, abolishing the intron 9 splice donor site. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in multiple individuals affected with MEN1 and primary hyperparathyroidism (PMID: 10090472, 16563611, 17065424, 27846313, 30324798). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MEN1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Nov 21, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.1350+1_1350+11del variant disrupts a canonical splice-donor site and interferes with normal MEN1 mRNA splicing. This variant has been reported in the published literature in individuals with multiple endocrine neoplasia type 1 (MEN1) syndrome (PMID: 30324798 (2018), 27846313 (2016), 16563611 (2006), 15714081 (2005), 10090472 (1999)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

May 21, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1350+1_1350+11delGTGAGGGACAG splice site mutation in the MEN1 gene has been previously reported in association with multiple endocrine neoplasia type 1 (Mutch et al., 1999). Using capital letters to denote exonic sequence and lower case letters to denote intronic sequence, the normal sequence with the bases that are deleted in braces is: ACAG{del gtgagggacag}ctgc. This mutation destroys the canonical splice donor site in intron 9, and is expected to cause abnormal gene splicing. The variant is found in MEN1 panel(s). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 14, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1350+1_1350+11del11 intronic pathogenic mutation, located in intron 8 of the MEN1 gene, results from a deletion of 11 nucleotides within intron 8 of the MEN1 gene. This alteration has been seen in multiple unrelated families with clinical diagnoses and features of MEN1 (Teh BT et al. J. Clin. Endocrinol. Metab.1998 Aug;83:2621-6; Jäger AC et al. Mol. Cell. Endocrinol. 2006 Apr;249:123-32; Kong J. PLoS ONE. 2016 Nov;11(11):e0166634). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs764570645; hg19: chr11-64572494;