11-64804503-C-T

Variant names:

• chr11-64804503-C-T
• rs863224527
• NM_001370259.2:c.1664G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1664G>A​(p.Ser555Asn) 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. S555R) has been classified as 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:7
• Conservation: PhyloP100: 3.75

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64804504-T-G is described in Lovd as [Pathogenic].
• 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, 0.793
• PP5: Variant 11-64804503-C-T is Pathogenic according to our data. Variant chr11-64804503-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64804503-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1664G>A	p.Ser555Asn	missense_variant	Exon 10 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1664G>A	p.Ser555Asn	missense_variant	Exon 10 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:4

Oct 09, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12112656, 9683585, 12807514]. Functional studies indicate this variant impacts protein function [PMID: 21819486, 22090276]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Jul 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 555 of the MEN1 protein (p.Ser555Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MEN1 (PMID: 9683585, 15254225). ClinVar contains an entry for this variant (Variation ID: 216134). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MEN1 function (PMID: 15254225, 21819486). For these reasons, this variant has been classified as Pathogenic. -

Dec 04, 2023

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.1664G>A (p.Ser555Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251390 control chromosomes. c.1664G>A has been reported in the literature in individuals affected with Multiple Endocrine Neoplasia Type 1 (Giraud_1998, Tso_2003, Wautot_2002). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a decrease in expression levels (Yaguchi_2004, Shimazu_2011). The following publications have been ascertained in the context of this evaluation (PMID: 9683585, 21819486, 12807514, 12112656, 15254225). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jul 02, 2018

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Pathogenic:1

Jan 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 30, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MEN1 c.1664G>A (p.Ser555Asn) variant has been reported in the published literature in individuals affected with MEN1 syndrome in the published literature (PMID: 9683585 (1998), 12112656 (2002), 12807514 (2003)). Functional studies indicated this variant causes reduced protein stability due to rapid degradation by the proteasome pathway (PMID: 15254225 (2004), 21819486 (2011), 22090276 (2012)).This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S555N pathogenic mutation (also known as c.1664G>A), located in coding exon 9 of the MEN1 gene, results from a G to A substitution at nucleotide position 1664. The serine at codon 555 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in numerous families with MEN1-related tumors, including parathyroid, pituitary and endocrine pancreatic tumors (Giraud S et al. Am. J. Hum. Genet. 1998 Aug; 63(2):455-67; Wautot V et al. Hum. Mutat. 2002 Jul; 20(1):35-47; Tso AW et al. Clin. Endocrinol. (Oxf) 2003 Jul; 59(1):129-35; Riechelmann RP et al. Endocr Relat Cancer, 2023 Jun;30:; Fainstein-Day P et al. Medicina (B Aires), 2024;84:433-444). In addition, cell-based functional assays have demonstrated reduced stability and expression of the menin protein compared with wild-type (Yaguchi H et al. Mol. Cell. Biol. 2004 Aug; 24(15):6569-80; Shimazu S et al. Cancer Sci. 2011 Nov; 102(11):2097-102). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant 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	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;D;D;D;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D;D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;M;M;M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.0070, 0.99, 0.99	.;B;D;D;D;D;D;D;D
Vest4		0.65
MutPred		0.51		.;.;.;.;.;Loss of phosphorylation at S560 (P = 0.0594);Loss of phosphorylation at S560 (P = 0.0594);Loss of phosphorylation at S560 (P = 0.0594);Loss of phosphorylation at S560 (P = 0.0594);
MVP		0.92
MPC		1.1
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.99

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: rs863224527; hg19: chr11-64571975;