NM_000268.4(NF2):c.947T>G (p.Leu316Trp) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Jun 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000268.4(NF2):c.947T>G (p.Leu316Trp)]

NM_000268.4(NF2):c.947T>G (p.Leu316Trp)

NF2:NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000268.4(NF2):c.947T>G (p.Leu316Trp)
  • NC_000022.11:g.29668394T>G
  • NG_009057.1:g.69839T>G
  • NM_000268.4:c.947T>GMANE SELECT
  • NM_016418.5:c.947T>G
  • NM_181825.3:c.947T>G
  • NM_181828.3:c.821T>G
  • NM_181829.3:c.824T>G
  • NM_181830.3:c.698T>G
  • NM_181831.3:c.698T>G
  • NM_181832.3:c.947T>G
  • NM_181833.3:c.447+26109T>G
  • NP_000259.1:p.Leu316Trp
  • NP_000259.1:p.Leu316Trp
  • NP_057502.2:p.Leu316Trp
  • NP_861546.1:p.Leu316Trp
  • NP_861966.1:p.Leu274Trp
  • NP_861967.1:p.Leu275Trp
  • NP_861968.1:p.Leu233Trp
  • NP_861969.1:p.Leu233Trp
  • NP_861970.1:p.Leu316Trp
  • LRG_511t1:c.947T>G
  • LRG_511t2:c.947T>G
  • LRG_511:g.69839T>G
  • LRG_511p1:p.Leu316Trp
  • LRG_511p2:p.Leu316Trp
  • NC_000022.10:g.30064383T>G
  • NM_000268.3:c.947T>G
  • NR_156186.2:n.1429T>G
Protein change:
dbSNP: rs750633919
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_181833.3:c.447+26109T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000268.4:c.947T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016418.5:c.947T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181825.3:c.947T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181828.3:c.821T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181829.3:c.824T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181830.3:c.698T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181831.3:c.698T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181832.3:c.947T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_156186.2:n.1429T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000674139Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jun 17, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain.

Shimizu T, Seto A, Maita N, Hamada K, Tsukita S, Tsukita S, Hakoshima T.

J Biol Chem. 2002 Mar 22;277(12):10332-6. Epub 2001 Dec 27.

PubMed [citation]

A functional association between merlin and HEI10, a cell cycle regulator.

Grönholm M, Muranen T, Toby GG, Utermark T, Hanemann CO, Golemis EA, Carpén O.

Oncogene. 2006 Jul 27;25(32):4389-98. Epub 2006 Mar 13.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000674139.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)


The p.L316W variant (also known as c.947T>G), located in coding exon 10 of the NF2 gene, results from a T to G substitution at nucleotide position 947. The leucine at codon 316 is replaced by tryptophan, an amino acid with similar properties. This alteration was reported in an individual with bilateral vestibular schwannomas (Ahronowitz I et al. Hum. Mutat. 2007 Jan;28(1):1-12). A structural analysis of L316W demonstrated that this alteration is exposed to solvent regions and, therefore, is unlikely to impact molecular function (Shimizu T et al. J. Biol. Chem. 2002 Mar;277:10332-6). Another study indicated that this alteration did not affect merlin binding to HEI10 (Grönholm M et al. Oncogene 2006 Jul;25(32):4389-98). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Dec 4, 2021

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