rs745404679

Variant names:

• chr11-64804549-G-A
• rs745404679
• NM_001370259.2:c.1618C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64804549-G-A
• chr11-64804549-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BS1_Supporting BS2

The NM_001370259.2(MEN1):​c.1618C>T​(p.Pro540Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,613,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P540I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:4
• Conservation: PhyloP100: 3.79
• Publications: 11 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: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 30 uncertain in NM_001370259.2
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25179446).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000138 (21/152278) while in subpopulation AMR AF = 0.00098 (15/15306). AF 95% confidence interval is 0.000604. There are 1 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370259.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.1618C>T	p.Pro540Ser	missense	Exon 10 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.1759C>T	p.Pro587Ser	missense	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1744C>T	p.Pro582Ser	missense	Exon 11 of 11	NP_001357180.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.1618C>T	p.Pro540Ser	missense	Exon 10 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.1618C>T	p.Pro540Ser	missense	Exon 10 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.1618C>T	p.Pro540Ser	missense	Exon 11 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 250902 AF XY: 0.0000884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461296 Hom.: 0 Cov.: 46 AF XY: 0.0000509 AC XY: 37 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111964

Other (OTH) AF: 0.000199 AC: 12 AN: 60388

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74444

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	3	-	not provided (4)
-	2	1	Multiple endocrine neoplasia, type 1 (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	Hereditary cancer (1)
-	1	-	Hyperparathyroidism (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.0092
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.25	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.69
Sift	Benign	0.16	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.31
MVP		0.94
MPC		1.1
ClinPred		0.18	T
GERP RS		4.3
Varity_R		0.049
gMVP		0.62
Mutation Taster		=1/99	disease causing

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: rs745404679; hg19: chr11-64572021; COSMIC: COSV105876348;