rs1555164245

Positions:

• chr11-64805105-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001370259.2(MEN1):​c.1279A>C​(p.Ser427Arg) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S427I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.92

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_001370259.2 (MEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64805104-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 11-64805105-T-G is Pathogenic according to our data. Variant chr11-64805105-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457285.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1279A>C	p.Ser427Arg	missense_variant	9/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1279A>C	p.Ser427Arg	missense_variant	9/10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

The p.S427R variant (also known as c.1279A>C), located in coding exon 8 of the MEN1 gene, results from an A to C substitution at nucleotide position 1279. The serine at codon 427 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in the literature in an individual with a clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) based on a personal history of hyperparathyroidism, pancreatic islet cell tumor and pituitary adenoma (Dackiw AP et al. Surgery, 1999 Dec;126:1097-103; discussion 1103-4). The p.S427R alteration has also been described in a family with multiple individuals affected with multiple endocrine neoplasia type 1 (MEN1) (Kouvaraki MA et al. Arch Surg. 2002;137:641-647). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Multiple endocrine neoplasia, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 15, 2019

In summary, this variant has uncertain impact on MEN1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals affected with multiple endocrine neoplasia type I (PMID: 12049533). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with arginine at codon 427 of the MEN1 protein (p.Ser427Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;D;D;D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;.;.;M;M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.75
MutPred		0.90		.;.;.;.;Loss of glycosylation at S432 (P = 0.0695);Loss of glycosylation at S432 (P = 0.0695);Loss of glycosylation at S432 (P = 0.0695);Loss of glycosylation at S432 (P = 0.0695);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.82
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555164245; hg19: chr11-64572577;