11-64805643-G-C

Variant names:

• chr11-64805643-G-C
• rs1060499984
• NM_001370259.2:c.1177C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001370259.2(MEN1):​c.1177C>G​(p.Gln393Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.76

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13139653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1177C>G	p.Gln393Glu	missense_variant	Exon 8 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1177C>G	p.Gln393Glu	missense_variant	Exon 8 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jan 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q393E variant (also known as c.1177C>G), located in coding exon 7 of the MEN1 gene, results from a C to G substitution at nucleotide position 1177. The glutamine at codon 393 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 1 Uncertain:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 393 of the MEN1 protein (p.Gln393Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 31159747). This variant is also known as c.1192C>G (p.Gln398Glu). ClinVar contains an entry for this variant (Variation ID: 403828). 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 not expected to disrupt MEN1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.22	T;.;.;.;.;D;D;D;D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T;T;.;.;T;.;.;T;.
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.0	.;.;.;.;.;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.45	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.64	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;B;B;B;B
Vest4		0.36
MutPred		0.33		.;.;.;.;.;Loss of glycosylation at S399 (P = 0.0873);Loss of glycosylation at S399 (P = 0.0873);Loss of glycosylation at S399 (P = 0.0873);Loss of glycosylation at S399 (P = 0.0873);
MVP		0.65
MPC		1.1
ClinPred		0.17	T
GERP RS		3.9
Varity_R		0.052
gMVP		0.70

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: rs1060499984; hg19: chr11-64573115; COSMIC: COSV53642626; COSMIC: COSV53642626;