rs386134248

chr11-64809985-CCCAGCA-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM4

The NM_001370259.2(MEN1):c.119_124del(p.Val40_Leu41del) variant causes a inframe deletion change. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V40V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.66

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001370259.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001370259.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.119_124del	p.Val40_Leu41del	inframe_deletion	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.119_124del	p.Val40_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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 08, 2018

Variant summary: MEN1 c.119_124delTGCTGG (p.Val40_Leu41del) results in an in-frame deletion that is predicted to remove two amino acids (Val, Leu) from the encoded protein. The variant was absent in 217338 control chromosomes (in 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.119_124delTGCTGG in individuals affected with Multiple Endocrine Neoplasia Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 10, 2018

This variant, c.119_124delTGCTGG, results in the deletion of 2 amino acid(s) of the MEN1 protein (p.Val40_Leu41del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with multiple endocrine neoplasia type 1 (PMID: 26767918). ClinVar contains an entry for this variant (Variation ID: 36522). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs386134248; hg19: chr11-64577457;