11-64807218-T-C

Variant names:

• chr11-64807218-T-C
• rs1555165373
• NM_001370259.2:c.785A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001370259.2(MEN1):​c.785A>G​(p.Lys262Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K262M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEN1 NM_001370259.2 missense, splice_region
• Scores: Splicing: ADA: 0.04517
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.54
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.785A>G	p.Lys262Arg	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.785A>G	p.Lys262Arg	missense_variant, splice_region_variant	Exon 5 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:3

May 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces lysine with arginine at codon 262 of the MEN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Feb 21, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 262 of the MEN1 protein (p.Lys262Arg). 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: 485718). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.785A>G (p.K262R) alteration is located in exon 5 (coding exon 4) of the MEN1 gene. This alteration results from a A to G substitution at nucleotide position 785, causing the lysine (K) at amino acid position 262 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.;.;D;D;D;D;D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;.;.;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.0	.;.;.;.;.;L;L;L;L;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;.;T
Polyphen		0.041, 0.33, 0.38	.;B;B;B;B;B;B;B;B;.;.
Vest4		0.21
MutPred		0.48		.;.;.;.;.;Loss of ubiquitination at K267 (P = 0.0218);Loss of ubiquitination at K267 (P = 0.0218);Loss of ubiquitination at K267 (P = 0.0218);Loss of ubiquitination at K267 (P = 0.0218);.;.;
MVP		0.86
MPC		0.86
ClinPred		0.74	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.63
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.045
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -1

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

Other links and lift over

dbSNP: rs1555165373; hg19: chr11-64574690;