rs104894256

Positions:

• chr11-64810045-A-C
• chr11-64810045-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.65T>G​(p.Leu22Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L22M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.65

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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64810046-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2760379.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-64810045-A-C is Pathogenic according to our data. Variant chr11-64810045-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64810045-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.65T>G	p.Leu22Arg	missense_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.65T>G	p.Leu22Arg	missense_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely 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	Apr 18, 1997	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 20, 2020	This sequence change replaces leucine with arginine at codon 22 of the MEN1 protein (p.Leu22Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect MEN1 protein function (PMID: 23580576, 22090276, 21819486, 21264250, 20404349, 19749796, 19074834). This variant has been observed to segregate with clinical features of multiple endocrine neoplasia type 1 in a family (Invitae). In addition, it has been reported in an individual affected with multiple endocrine neoplasia type 1 (PMID: 9103196), and in an individual with a lipoma (PMID: 9498491). ClinVar contains an entry for this variant (Variation ID: 16677). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	Published functional studies demonstrate a damaging effect: reduced protein expression and stability, inability to repress JunD-mediated transcription or Gas1 expression in Hedgehog signaling (Agarwal et al., 1999; Canaff et al., 2012; Gurung et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21264250, 19074834, 22090276, 9989505, 23580576, 9498491, 16195383, 14992727, 17879353, 15281352, 9681840, 9215689, 10730900, 21916912, 21819486, 19596783, 17766243, 20404349, 20639902, 12509449, 22878668, 15640349, 18598942, 21252315, 12112656, 17953629, 9103196, 30869828) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen		0.97, 1.0	.;D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.93		Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);Loss of stability (P = 0.0406);
MVP		1.0
MPC		2.6
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894256; hg19: chr11-64577517; COSMIC: COSV56343221; COSMIC: COSV56343221;