rs386134249

Positions:

• chr11-64805122-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1262G>A​(p.Cys421Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.83

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.985
• PP5: Variant 11-64805122-C-T is Pathogenic according to our data. Variant chr11-64805122-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64805122-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1262G>A	p.Cys421Tyr	missense_variant	9/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1262G>A	p.Cys421Tyr	missense_variant	9/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 55 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 421 of the MEN1 protein (p.Cys421Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MEN1-related conditions (PMID: 15714081; Invitae). ClinVar contains an entry for this variant (Variation ID: 36523). 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. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 15, 2021	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2017	The MEN1 c.1262G>A;p.Cys421Tyr variant has been published in the literature in one individual with a clinical diagnosis of MEN1 (Klein 2005). Additionally, ARUP laboratories has detected this variant in an individual with a clinical diagnosis of MEN1. The variant is listed in the dbSNP variant database (rs386134249) and the ClinVar database (Variation ID: 36523), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The cysteine at position 421 is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Taken together, this variant is considered likely pathogenic. References: Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 7(2):131-8. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2023	Not observed at significant frequency in large population cohorts (gnomAD); 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: 17039269, 15714081, 17879353, 9989505, 34183184, 35428475) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2019

The p.C421Y variant (also known as c.1262G>A), located in coding exon 8 of the MEN1 gene, results from a G to A substitution at nucleotide position 1262. The cysteine at codon 421 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in a series of patient samples submitted for MEN1 gene sequencing, and was presumed to be pathogenic due to its absence in 200 unaffected individuals, alteration of highly conserved base-pairs, and/or segregation within a family (Klein RD et al., Genet. Med. 2005 Feb; 7(2):131-8). 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	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;D;D;D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;.;.;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-9.4	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.93
MutPred		0.87		.;.;.;.;Gain of phosphorylation at C426 (P = 0.0341);Gain of phosphorylation at C426 (P = 0.0341);Gain of phosphorylation at C426 (P = 0.0341);Gain of phosphorylation at C426 (P = 0.0341);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.97
gMVP		1.0

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: rs386134249; hg19: chr11-64572594;