rs1114167480

Variant names:

• chr11-64806268-A-G
• rs1114167480
• NM_001370259.2:c.1013T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-64806268-A-G
• chr11-64806268-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1013T>C​(p.Leu338Pro) 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. L338V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.24

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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001370259.2
• 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, 0.937
• PP5: Variant 11-64806268-A-G is Pathogenic according to our data. Variant chr11-64806268-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64806268-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1013T>C	p.Leu338Pro	missense_variant	Exon 7 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1013T>C	p.Leu338Pro	missense_variant	Exon 7 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 01, 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.1013T>C; p.Leu338Pro variant (rs1114167480) is reported in the literature in individuals affected with multiple endocrine neoplasia, type 1 (Koyama 2022, Tham 2007). This variant was also found to segregate in family members affected with hyperparathyroidism and insulinoma (Koyama 2022, Tham 2007). This variant is also reported in ClinVar (Variation ID: 428016) and 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: 0.937). Based on available information, this variant is considered to be likely pathogenic. References: Koyama N et al. Multiple Endocrine Neoplasia Type 1 with Functional Parathyroid Cysts. Intern Med. 2022 Apr 15;61(8):1183-1188. PMID: 34645755. Tham E et al. Clinical testing for mutations in the MEN1 gene in Sweden: a report on 200 unrelated cases. J Clin Endocrinol Metab. 2007 Sep;92(9):3389-95. PMID: 17623761. -

May 08, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The L338P variant in the MEN1 gene has previously been published in at least one individual with multiple endocrine neoplasia type 1 (Tham et al., 2007). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L338P 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 is located within the region of interaction with FANCD2 (Uniprot). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, L338P 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

Apr 21, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L338P variant (also known as c.1013T>C) is located in coding exon 6 of the MEN1 gene. This alteration results from a T to C substitution at nucleotide position 1013. The leucine at codon 338 is replaced by proline, an amino acid with similar properties. In a study of 200 unrelated Swedish index cases, this variant was reported in three affected members of one family. The proband was diagnosed with primary hyperparathyroidism with hyperplasia, an endocrine enteropancreatic gastrinoma, and an anterior pituitary tumor. The family members were diagnosed with hyperparathyriodism and insulinoma (Tham et al. J of Clinical Endocrinology & Metab. 2007. 92(9):3389-3395). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 7000 alleles tested) in our clinical cohort. Based on protein sequence alignment, 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	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;D;D;D;D;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;.;.;D;.;.;D;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;M;M;M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.050	T;D;D;D;D;D;D;D;D;.
Polyphen		1.0, 1.0	.;D;D;D;D;D;D;D;D;.
Vest4		0.86
MutPred		0.75		.;.;.;.;.;Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);.;
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1114167480; hg19: chr11-64573740; COSMIC: COSV53643997; COSMIC: COSV53643997;