rs1555166695

Positions:

• chr11-64809987-CAGCACCAAGGAAAGG-C
• chr11-64809987-CAGCACCAAGGAAAGG-CAGCACCAAGGAAAGGAGCACCAAGGAAAGG

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.108_122del​(p.Leu37_Leu41del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L36L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.49

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001370259.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-64809987-CAGCACCAAGGAAAGG-C is Pathogenic according to our data. Variant chr11-64809987-CAGCACCAAGGAAAGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64809987-CAGCACCAAGGAAAGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.108_122del	p.Leu37_Leu41del	inframe_deletion	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.108_122del	p.Leu37_Leu41del	inframe_deletion	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This variant, c.108_122del, results in the deletion of 5 amino acid(s) of the MEN1 protein (p.Leu37_Leu41del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 428044). This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Ser38Phe) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2019

The c.108_122del15 variant (also known as p.L37_L41del) is located in coding exon 1 of the MEN1 gene. This variant results from an in-frame deletion of 15 nucleotides (CCTTTCCTTGGTGCT) at positions 108 to 122. This results in the deletion of five amino acids (LSLVL) between codons 37 and 41. This alteration has been detected in an individual with a clinical history that is consistent with MEN1 (Ambry internal data). Based on an internal structural assessment, this variant is anticipated to result in a significant decrease in structural stability. The amino acid positions deleted in this alteration are highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555166695; hg19: chr11-64577459;