11-64807093-G-T

Variant names:

• chr11-64807093-G-T
• rs1060499973
• NM_001370259.2:c.830C>A

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.830C>A​(p.Pro277His) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 Pathogenic. Variant got 15 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-64807093-G-T is Pathogenic according to our data. Variant chr11-64807093-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 403801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64807093-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.830C>A	p.Pro277His	missense_variant	Exon 6 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.830C>A	p.Pro277His	missense_variant	Exon 6 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:2

Dec 10, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEN1 c.830C>A (p.Pro277His) 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 251000 control chromosomes (gnomAD). c.830C>A has been reported in the literature in at-least two individuals affected with features of Multiple Endocrine Neoplasia Type 1 (specifically primary hyperparathyroidism (HPT) and pancreatic tumor) from a family reporting several other non-genotyped affected individuals with similar clinical indications, as well as an affected individual without the variant (Perrier_2002). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Shimazu_2011). The most pronounced variant effect results in decreased stability (approximately 20% of WT levels). The following publications have been ascertained in the context of this evaluation (PMID: 12699448, 12016470, 21819486). ClinVar contains an entry for this variant (Variation ID: 403801). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 277 of the MEN1 protein (p.Pro277His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MEN1-associated endocrine tumors and/or primary hyperparathyroidism (PMID: 12016470; internal data). ClinVar contains an entry for this variant (Variation ID: 403801). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MEN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MEN1 function (PMID: 21819486). This variant disrupts the p.Pro277 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been observed in individuals with MEN1-related conditions (PMID: 37484956), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Jul 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.830C>A; p.Pro277His variant (rs1060499973, ClinVar Variation ID: 403801) is reported in the literature in multiple individuals affected with features of multiple endocrine neoplasia type 1 (Concolino 2016, Pierotti 2023, Perrier 2002). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.979). Functional analyses of the variant protein show reduced stability and expression of the menin protein compared with wild-type (Shimazu 2011). Based on available information, this variant is considered to be likely pathogenic. References: Concolino P et al. Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. Cancer Genet. 2016 Jan-Feb;209(1-2):36-41. PMID: 26767918. Pierotti L et al. Cutaneous lesions and other non-endocrine manifestations of Multiple Endocrine Neoplasia type 1 syndrome. Front Endocrinol (Lausanne). 2023 Jul 7;14:1191040. PMID: 37484956. Perrier ND et al. Genetic screening for MEN1 mutations in families presenting with familial primary hyperparathyroidism. World J Surg. 2002 Aug;26(8):907-13. PMID: 12016470. Shimazu S et al. Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. Cancer Sci. 2011 Nov;102(11):2097-102. PMID: 21819486. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 20, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P277H variant (also known as c.830C>A), located in coding exon 5 of the MEN1 gene, results from a C to A substitution at nucleotide position 830. The proline at codon 277 is replaced by histidine, an amino acid with similar properties. This alteration was detected in a family with features of multiple endocrine neoplasia type 1 (MEN1), including hyperparathyroidism and elevated gastrin levels (Perrier et al. World J. Surg. 2002 Aug; 26(8):907-13). Furthermore, functional studies have demonstrated reduced stability and expression of the menin protein compared with wild-type (Shimazu S et al. Cancer Sci. 2011. Nov;102(11):2097-102). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;D;D;D;D;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;.;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;M;M;M;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.3	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	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
Polyphen		1.0	.;D;D;D;D;D;D;D;D;.;.
Vest4		0.89
MutPred		0.92		.;.;.;.;.;Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);.;.;
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.97

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: rs1060499973; hg19: chr11-64574565;