11-64807890-C-T

Variant names:

• chr11-64807890-C-T
• rs794728622
• NM_001370259.2:c.654+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.654+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: 32)
• Consequence: MEN1 NM_001370259.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.90
• Publications: 3 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, Cryptic splice site detected, with MaxEntScore 5, offset of -14, new splice context is: ccgGTgtgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64807890-C-T is Pathogenic according to our data. Variant chr11-64807890-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39763.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.654+1G>A		splice_donor_variant, intron_variant	Intron 3 of 9	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.654+1G>A		splice_donor_variant, intron_variant	Intron 3 of 9	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Jun 04, 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 3 of the MEN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 35 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 1 (MEN1) syndrome (PMID: 22275377, 25733923, 28870973). This variant is also known as IVS3+1G>A. ClinVar contains an entry for this variant (Variation ID: 39763). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 3 (PMID: 22275377). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Trp183Cys) have been determined to be pathogenic (PMID: 11524904, 16699310, 22281890). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 09, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jan 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant expected to result in aberrant splicing; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate in-frame loss of 35 amino acids disrupting TGF-B signaling and leading to reduced activation of p15 and p21 as well as increased cell proliferation (Canaff et al., 2012); This variant is associated with the following publications: (PMID: 22275377, 25733923, 30339208, 28870973) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 25, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.654+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MEN1 gene. This alteration has been detected in an individual with multiple endocrine neoplasia type 1 (MEN1) syndrome (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). RNA studies showed that the c.654+1G>A variant leads to an alternatively spliced transcript with a 35 amino acid deletion (Canaff L et al. J. Biol. Chem., 2012 Mar;287:8584-97). In addition, functional studies conducted by this same group showed that lymphoblastoid cells expressing the resulting mutant protein showed increased cell proliferation and had a defective TGF-β response. Another variant at this donor site, c.654+1G>T, has also been detected in multiple unrelated families with MEN1 (Teh BT et al. J. Clin. Endocrinol. Metab., 1998 Aug;83:2621-6; Ambry Internal Data). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.9
GERP RS		4.7
PromoterAI		0.051	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 15
DS_DL_spliceai		0.97		Position offset: 1

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

Other links and lift over

dbSNP: rs794728622; hg19: chr11-64575362; COSMIC: COSV53649214; COSMIC: COSV53649214;