rs794728624

Variant names:

• chr11-64807613-C-T
• rs794728624
• NM_001370259.2:c.722G>A

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.722G>A​(p.Cys241Tyr) 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. C241F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.86

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 chr11-64807613-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 11-64807613-C-T is Pathogenic according to our data. Variant chr11-64807613-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807613-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.722G>A	p.Cys241Tyr	missense_variant	Exon 4 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.722G>A	p.Cys241Tyr	missense_variant	Exon 4 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys241 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10090472, 12652570, 20231234; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 200980). This missense change has been observed in individuals with familial multiple endocrine neoplasia type 1 (PMID: 10576763, 17853334; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 241 of the MEN1 protein (p.Cys241Tyr). -

not provided Pathogenic:1

Feb 12, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.722G>A; p.Cys241Tyr variant (rs794728624) is reported in the literature in an individual with a clinical diagnosis of MEN1 (Hai 1999), and is reported in the ClinVar database (Variation ID: 200980). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 241 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two other variants at this codon (Cys241Arg, Cys241Phe) are reported in individuals with MEN1 (Crepin 2003, Ellard 2005, Mutch 1999, see ClinVar Variation ID: 659647). Based on available information, the p.Cys241Tyr variant is considered to be likely pathogenic. REFERENCES Crepin M et al. Efficient mutation detection in MEN1 gene using a combination of single-strand conformation polymorphism (MDGA) and heteroduplex analysis. Electrophoresis. 2003 Jan;24(1-2):26-33. Ellard S et al. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol (Oxf). 2005 Feb;62(2):169-75. Hai N et al. Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1). Eur J Endocrinol. 1999 Nov;141(5):475-80. Mutch MG et al. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Hum Mutat. 1999;13(3):175-85. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 06, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C241Y variant (also known as c.722G>A), located in coding exon 3 of the MEN1 gene, results from a G to A substitution at nucleotide position 722. The cysteine at codon 241 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was detected in a familial MEN1 patient from Japan who had a personal history of parathyroid, pancreatic neuroendocrine, and adrenal tumors (Hai N et al. Eur. J. Endocrinol. 1999 Nov;141:475-80). In addition, two other alterations at the same codon, p.C241R and p.C241F, have also been detected MEN1 cohorts from the literature (Mutch MG et al. Hum. Mutat. 1999;13:175-85; Crépin M et al. Electrophoresis. 2003 Jan;24:26-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.;.;D;D;D;D;D;.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;.;.;D;.;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	.;.;.;.;.;M;M;M;M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.028	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D;.;D;D
Polyphen		1.0, 0.97, 0.98	.;D;D;D;D;D;D;D;D;.;.;.
Vest4		0.93
MutPred		0.90		.;.;.;.;.;Loss of catalytic residue at M244 (P = 5e-04);Loss of catalytic residue at M244 (P = 5e-04);Loss of catalytic residue at M244 (P = 5e-04);Loss of catalytic residue at M244 (P = 5e-04);.;.;.;
MVP		0.99
MPC		2.7
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.99

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: rs794728624; hg19: chr11-64575085;