11-64810109-T-G

Variant names:

• chr11-64810109-T-G
• rs386134250
• NM_001370259.2:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1A>C​(p.Met1?) variant causes a initiator codon 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEN1 NM_001370259.2 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.25
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 256 pathogenic variants. Next in-frame start position is after 228 codons. Genomic position: 64807653. Lost 0.372 part of the original CDS.
• PS1: Another start lost variant in NM_001370259.2 (MEN1) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64810109-T-G is Pathogenic according to our data. Variant chr11-64810109-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 850884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1A>C	p.Met1?	initiator_codon_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	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.0000374 AC: 6 AN: 160466 AF XY: 0.0000222

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000828

Gnomad FIN exome AF: 0.000115

Gnomad NFE exome AF: 0.0000138

Gnomad OTH exome AF: 0.000252

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000242 AC: 243 AN: 1005232 Hom.: 0 Cov.: 36 AF XY: 0.000279 AC XY: 135 AN XY: 484064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000389 AC: 9 AN: 23124

American (AMR) AF: 0.000285 AC: 8 AN: 28086

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 2 AN: 13100

East Asian (EAS) AF: 0.000362 AC: 5 AN: 13828

South Asian (SAS) AF: 0.000778 AC: 37 AN: 47558

European-Finnish (FIN) AF: 0.000636 AC: 8 AN: 12578

Middle Eastern (MID) AF: 0.000318 AC: 1 AN: 3146

European-Non Finnish (NFE) AF: 0.000183 AC: 152 AN: 829266

Other (OTH) AF: 0.000608 AC: 21 AN: 34546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

Alfa AF: 0.000370 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Pathogenic:1

Mar 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the MEN1 mRNA. The next in-frame methionine is located at codon 228. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with multiple endocrine neoplasia, type 1 (PMID: 28736585, 29036195; Invitae; UMD). ClinVar contains an entry for this variant (Variation ID: 850884). For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 07, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>C) is located in coding exon 1 of the MEN1 gene and results from a A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Different substitutions impacting the same initiation codon (c.1A>G, c.1A>T, c.2T>C and c.2T>G) have been detected in individuals with features or clinical diagnoses of multiple endocrine neoplasia type 1 and familial isolated hyperparathyroidism (Ambry internal data; Villablanca A et al. Eur. J. Endocrinol. 2002 Sep;147(3):313-22; Klein RD et al. Genet. Med. 2005 Feb;7(2):131-8; Ventura M et al. Arch Endocrinol Metab, 2019 Sep;63:516-523; Romanet P et al. J Clin Endocrinol Metab, 2019 03;104:753-764). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T;.;.;.;.;T;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		4.3
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.024	D;D;D;D;D;D;D;D;D;D;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Vest4		0.69
ClinPred		0.52	D
GERP RS		4.2
PromoterAI		-0.35	Neutral
Varity_R		0.63
gMVP		0.52
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386134250; hg19: chr11-64577581;