11-64805666-G-A

Position:

• chr11-64805666-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001370259.2(MEN1):​c.1154C>T​(p.Ala385Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:1
• Conservation: PhyloP100: 2.01

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]

MEN1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1154C>T	p.Ala385Val	missense_variant	8/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1154C>T	p.Ala385Val	missense_variant	8/10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251284 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461756 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This missense variant replaces alanine with valine at codon 385 of the MEN1 protein. This variant is also known as c.1169C>T (p.Ala390Val) in the literature. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two unrelated individuals affected with hyperparathyroidism and/or MEN1-associated clinical features (PMID: 10849016, 14641000, 22470073). This variant has been identified in 1/251284 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 24, 2023	- -

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2024

The c.1154C>T variant (also known as p.A385V), located in coding exon 7 of the MEN1 gene, results from a C to T substitution at nucleotide position 1154. The alanine at codon 385 is replaced by valine, an amino acid with similar properties. This alteration has been reported in Dutch individuals with suspected multiple endocrine neoplasia type 1 (Roijers JF et al. Eur. J. Clin. Invest. 2000 Jun;30(6):487-92; Geerdink EA et al. Eur J Endocrinol, 2003 Dec;149:577-82; Pieterman CR et al. Ann. Surg. 2012 Jun;255(6):1171-8). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 10 amino acid(s); however, the exact functional impact of the deleted amino acid(s) is unknown at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.;.;.;D;D;D;D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;.;.;D;.;.;D;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.1	.;.;.;.;.;L;L;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.010	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.22	T;D;D;D;D;D;D;D;D
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T
Polyphen		0.031, 0.10, 0.039	.;B;B;B;B;B;B;B;B
Vest4		0.38
MutPred		0.58		.;.;.;.;.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.97
MPC		1.1
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.18
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1298484645; hg19: chr11-64573138;