11-64809909-GGGGCT-GGGGCTGGGCT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):c.200_201insAGCCC(p.Asp70ProfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P67P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MEN1 NM_001370259.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.76

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64809909-G-GGGGCT is Pathogenic according to our data. Variant chr11-64809909-G-GGGGCT is described in ClinVar as [Pathogenic]. Clinvar id is 403814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.200_201insAGCCC	p.Asp70ProfsTer51	frameshift_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.200_201insAGCCC	p.Asp70ProfsTer51	frameshift_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 23, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Asp70Profs*51) in the MEN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MEN1 are known to be pathogenic (PMID: 12112656, 17853334). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9683585, 22026581, 24959251, 25309785). ClinVar contains an entry for this variant (Variation ID: 403814). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 24, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 25, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Dec 20, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2022

The c.196_200dupAGCCC pathogenic mutation, located in coding exon 1 of the MEN1 gene, results from a duplication of AGCCC at nucleotide position 196, causing a translational frameshift with a predicted alternate stop codon (p.D70Pfs*51). This mutation has been reported in multiple individuals with clinical features of MEN1 (Giraud S et al. Am. J. Hum. Genet. 1998 Aug;63:455-67; Park JH et al. Clin. Genet. 2003 Jul;64:48-53; Belar O et al. Clin. Endocrinol. (Oxf) 2012 May;76:719-24; Jeong YJ et al. Oncol. Lett. 2014 Jul;8:230-234; Chung YJ et al. Endocrinol. Metab. (Seoul) 2014 Sep;29:270-9). Of note, this alteration is also designated as 310dup5-ter120 and 200-201insAGCCC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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: rs1555166609; hg19: chr11-64577381;