11-64809879-G-C

Variant names:

• chr11-64809879-G-C
• rs1555166567
• NM_001370259.2:c.231C>G

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.231C>G​(p.Tyr77*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEN1 NM_001370259.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.69

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 11-64809879-G-C is Pathogenic according to our data. Variant chr11-64809879-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 527270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809879-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.231C>G	p.Tyr77*	stop_gained	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.231C>G	p.Tyr77*	stop_gained	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Apr 27, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). This variant has been reported in an individual or family undergoing MEN1 genetic testing (PMID: 15714081). ClinVar contains an entry for this variant (Variation ID: 527270). This sequence change creates a premature translational stop signal (p.Tyr77*) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. -

Dec 13, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEN1 c.231C>G (p.Tyr77X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (example: c.228delC [p.Tyr77ThrfsX42], c.292C>T [p.Arg98X]). The variant was absent in 223538 control chromosomes. c.231C>G has been reported in the literature in individuals affected with Multiple Endocrine Neoplasia Type 1 (example: Kovesdi_2019, Isailovic_2019, Klein_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

May 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual undergoing testing for Multiple Endocrine Neoplasia type 1 (Klein 2005); This variant is associated with the following publications: (PMID: 25525159, 15714081) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 16, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y77* pathogenic mutation (also known as c.231C>G), located in coding exon 1 of the MEN1 gene, results from a C to G substitution at nucleotide position 231. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This mutation has been previously reported in individuals with multiple endocrine neoplasia type 1 (MEN1) (Klein RD et al. Genet. Med., 2005 Feb;7:131-8; Isailovic T et al. J Med Biochem, 2019 Mar;38:38-44). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted 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	0.54
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.84
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555166567; hg19: chr11-64577351;