11-64807890-C-T

Position:

• chr11-64807890-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.654+1G>A variant causes a splice donor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.90

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 22 ACMG points.

• PVS1: Splicing 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-64807890-C-T is Pathogenic according to our data. Variant chr11-64807890-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.654+1G>A		splice_donor_variant		ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.654+1G>A		splice_donor_variant		5	NM_001370259.2	P3

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2019	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22275377). This variant has been observed in several individuals and families affected with clinical features of multiple endocrine neoplasia type 1 (MEN1) syndrome (PMID: 22275377, 25733923, 28870973). This variant is also known as IVS3+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 39763). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the MEN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2020

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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
GERP RS		4.7

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

Publications

LitVar

Other links and lift over

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