rs1555165268

chr11-64807031-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370259.2(MEN1):c.892C>G(p.Pro298Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P298L) has been classified 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:2
• Conservation: PhyloP100: 8.15

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MEN1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.892C>G	p.Pro298Ala	missense_variant	6/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.892C>G	p.Pro298Ala	missense_variant	6/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 08, 2019

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has not been reported in the literature in individuals with MEN1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 298 of the MEN1 protein (p.Pro298Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2022

The p.P298A variant (also known as c.892C>G), located in coding exon 5 of the MEN1 gene, results from a C to G substitution at nucleotide position 892. The proline at codon 298 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	22
Dann	Benign	0.88
DEOGEN2	Uncertain	0.57	D;.;.;.;.;D;D;D;D;D
Eigen	Benign	0.0067
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;.;.;D;.;.;D;.;D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.45	N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.65
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.90	T;T;T;T;T;T;T;T;T;.
Polyphen		1.0, 0.15, 0.18	.;D;B;B;B;B;B;B;B;.
Vest4		0.60
MutPred		0.60		.;.;.;.;.;Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);.;
MVP		0.88
MPC		1.2
ClinPred		0.77	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555165268; hg19: chr11-64574503;