rs1064793169

Positions:

• chr11-64806359-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001370259.2(MEN1):​c.922T>C​(p.Ser308Pro) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.11

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.922
• PP5: Variant 11-64806359-A-G is Pathogenic according to our data. Variant chr11-64806359-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418293.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.922T>C	p.Ser308Pro	missense_variant	7/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.922T>C	p.Ser308Pro	missense_variant	7/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2016

The S308P variant in the MEN1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S308P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and within the region of interaction with FANCD2 (Uniprot). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G305R, G305D, A309P, T311P) have been reported in the Human Gene Mutation Database in association with MEN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available evidence, the S308P variant is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2021

The p.S308P variant (also known as c.922T>C), located in coding exon 6 of the MEN1 gene, results from a T to C substitution at nucleotide position 922. The serine at codon 308 is replaced by proline, an amino acid with similar properties. This alteration has been detected in multiple individuals with a clinical diagnosis and family histories consistent with Multiple Endocrine Neoplasia Type 1 (MEN1) (Ambry internal data). Based on internal structural analysis, this variant results in a decrease in structural stability (Huang J et al. Nature, 2012 Feb;482:542-6). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;D;D;D;D;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D;.;.;D;.;.;D;.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.012	D;D;D;D;D;D;D;D;D;T
Sift4G	Benign	0.061	T;T;D;D;D;D;D;D;D;.
Polyphen		0.99, 1.0	.;D;D;D;D;D;D;D;D;.
Vest4		0.90
MutPred		0.80		.;.;.;.;.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;
MVP		0.98
MPC		2.4
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.92
gMVP		0.98

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: rs1064793169; hg19: chr11-64573831;