11-64808079-C-G

Position:

• chr11-64808079-C-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.466G>C​(p.Gly156Arg) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G156S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.05

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 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64808079-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 988303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-64808079-C-G is Pathogenic according to our data. Variant chr11-64808079-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 426144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64808079-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.466G>C	p.Gly156Arg	missense_variant	3/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.466G>C	p.Gly156Arg	missense_variant	3/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely 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

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

Feb 06, 2023

Variant summary: MEN1 c.466G>C (p.Gly156Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Other variants located at the same codon have been reported in association with Multiple Endocrine Neoplasia Type 1 in the HGMD database, supporting a critical role of this location in Menin, the MEN1 encoded protein. The variant was absent in 246660 control chromosomes. c.466G>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (example, PMID: 17766710, 28458907). Recently the French oncogenetics network of neuroendocrine tumors (TENGEN) has proposed this variant be classified as pathogenic using adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants (PMID: 30869828). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2018

The G156R variant in the MEN1 gene has previously been reported in multiple individuals with multiple endocrine neoplasia type 1 (Vierimaa et al., 2007; Uraki et al., 2017). This variant is not observed in large population cohorts (Lek et al., 2016). The G156R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G156S, G156C, G156V, G156D), as well as nearby residues (D153Y, D153V, D153E, S154I, S155F, A158D, A160P, A160T) have been reported in the Human Gene Mutation Database in association with MEN1-related disorders (Mutch et al., 1999; Tham et al., 2007; Belar et al., 2012; Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;D;D;D;D;D;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.7	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D
Polyphen		1.0	.;D;D;D;D;D;D;D;D;.;.;.
Vest4		0.99
MutPred		0.93		.;.;.;.;.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;.;.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1085307471; hg19: chr11-64575551;