11-64807654-G-T

Position:

• chr11-64807654-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.681C>A​(p.Tyr227Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.35

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64807654-G-T is Pathogenic according to our data. Variant chr11-64807654-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 457331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807654-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.681C>A	p.Tyr227Ter	stop_gained	4/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.681C>A	p.Tyr227Ter	stop_gained	4/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2020

This sequence change creates a premature translational stop signal (p.Tyr227*) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 17853334, 10534569, 17879353). This variant has been observed in an individual from a family with multiple endocrine neoplasia type 1 (PMID: 9709921). ClinVar contains an entry for this variant (Variation ID: 457331). This variant is not present in population databases (ExAC no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Jun 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.98
GERP RS		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs778921501; hg19: chr11-64575126;