11-64810075-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5

The NM_001370259.2(MEN1):c.35C>G(p.Pro12Arg) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.16

Variant links:

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]

MEN1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-64810075-G-A 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, 0.944

PP5

Variant 11-64810075-G-C is Pathogenic according to our data. Variant chr11-64810075-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1733068.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2 link	c.35C>G	p.Pro12Arg	missense_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7 link	c.35C>G	p.Pro12Arg	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3		O00255-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 1

Pathogenic:1

Dec 17, 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 arginine, which is basic and polar, at codon 12 of the MEN1 protein (p.Pro12Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 1 (internal data). ClinVar contains an entry for this variant (Variation ID: 1733068). 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%. This variant disrupts the p.Pro12 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9215689, 12509449, 15254225, 21264250, 21819486, 22090276; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Apr 02, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21819486, 29122330, 21264250, 9989505, 15254225, 22090276, 9215689, 12509449) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jan 20, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P12R variant (also known as c.35C>G), located in coding exon 1 of the MEN1 gene, results from a C to G substitution at nucleotide position 35. The proline at codon 12 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in one individual with a pancreatic neuorendocrine tumor and hyperparathyroidism and another with pituitary adenoma and hyperparathyroidism (Ambry internal data). 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, 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. -

not specified

Uncertain:1

Sep 11, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MEN1 c.35C>G (p.Pro12Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 231760 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.35C>G in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29122330). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.;.;D;D;D;D;D;.;D;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;.;.;D;.;.;D;.;D;D;D;.;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

.;M;M;M;M;M;M;M;M;.;.;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.5

D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;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

0.74, 1.0

.;P;D;D;D;D;D;D;D;.;.;.;.;.

Vest4

0.94

MutPred

0.75

Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);

MVP

1.0

MPC

2.3

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.87

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over