11-64810109-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_001370259.2(MEN1):c.1A>C(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.25

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: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001370259.2 (MEN1) was described as [Likely_pathogenic] in ClinVar as 188376
• PP5: Variant 11-64810109-T-G is Pathogenic according to our data. Variant chr11-64810109-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 850884.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.1A>C	p.Met1?	start_lost	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1A>C	p.Met1?	start_lost	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 28

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

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000285

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.000362

Gnomad4 SAS exome AF: 0.000778

Gnomad4 FIN exome AF: 0.000636

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome Cov.: 28

Alfa AF: 0.00134 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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 02, 2021

For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individuals with multiple endocrine neoplasia, type 1 (PMID: 28736585, 29036195; Invitae; UMD). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the MEN1 mRNA. The next in-frame methionine is located at codon 228. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2023

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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
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;.;.
Polyphen		0.65, 0.70	.;P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.69
MutPred		0.73		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.99
ClinPred		0.52	D
GERP RS		4.2
Varity_R		0.63
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs386134250; hg19: chr11-64577581;