11-64808019-C-G

Position:

• chr11-64808019-C-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001370259.2(MEN1):​c.526G>C​(p.Ala176Pro) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.983
• PP5: Variant 11-64808019-C-G is Pathogenic according to our data. Variant chr11-64808019-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64808019-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.526G>C	p.Ala176Pro	missense_variant	3/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.526G>C	p.Ala176Pro	missense_variant	3/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MEN1 function (PMID: 9989505, 11221882, 12509449, 19074834, 22090276, 23648481). 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 expected to disrupt MEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 200975). This missense change has been observed in individuals with MEN1-related conditions (PMID: 9215689; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 176 of the MEN1 protein (p.Ala176Pro). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2023	Variant summary: MEN1 c.526G>C (p.Ala176Pro) 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. The variant was absent in 251222 control chromosomes (gnomAD). c.526G>C has been reported in the literature in individuals affected with Multiple Endocrine Neoplasia Type 1 (example: Agarwal_1998). Multiple publications have reported experimental evidence that this variant disrupts the normal activity of the protein (examples: Agarwal_1999, Chen_2008, Canaff_2012, Fang_2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2017

The A176P missense variant in the MEN1 gene has previously been published in association with multiple endocrine neoplasia type 1 (Agarwal et al., 1997; Marx et al., 1998). Functional studies demonstrate that A176P results in reduced protein expression compared to wild-type, and that the resulting protein product is unstable (Canaff et al., 2012). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A176P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, A176P is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2020

The p.A176P pathogenic mutation (also known as c.526G>C), located in coding exon 2 of the MEN1 gene, results from a G to C substitution at nucleotide position 526. The alanine at codon 176 is replaced by proline, an amino acid with highly similar properties. This mutation has been reported in several individuals with multiple endocrine neoplasia type 1 (MEN1) (Agarwal S et al. Hum. Mol. Genet. 1997 Jul; 6(7):1169-75; Ambry internal data). This mutation has also been the subject of numerous functional studies finding disruptions in the JunD and Wnt/β-catenin signaling pathways, abolishment of menin-RPA2 interaction, impaired homologous recombination-directed DNA repair, and selective targeting of this mutant protein for degradation in the proteosome (Agarwal S et al. Cell 1999 Jan; 96(1):143-52; Sukhodolets KE et al. Mol. Cell. Biol., 2003 Jan;23:493-509; Chen G et al. Mol. Cancer Res. 2008 Dec; 6(12):1894-907; Canaff L et al. J. Clin. Endocrinol. Metab. 2012 Feb; 97(2); Fang M et al. Mol. Cell. Biol. 2013 Jul; 33(13):2635-47). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;D;D;D;D;D;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;.;D;D
Polyphen		1.0	.;D;D;D;D;D;D;D;D;.;.;.
Vest4		0.94
MutPred		0.91		.;.;.;.;.;Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
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: rs376872829; hg19: chr11-64575491;