NM_001042492.3(NF1):c.5906A>T (p.Gln1969Leu) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 3, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001818379.6

Allele description [Variation Report for NM_001042492.3(NF1):c.5906A>T (p.Gln1969Leu)]

NM_001042492.3(NF1):c.5906A>T (p.Gln1969Leu)

Gene:

NF1:neurofibromin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q11.2

Genomic location:

Preferred name:

NM_001042492.3(NF1):c.5906A>T (p.Gln1969Leu)

HGVS:

NC_000017.11:g.31334931A>T
NG_009018.1:g.244955A>T
NM_000267.3:c.5843A>T
NM_001042492.3:c.5906A>TMANE SELECT
NP_000258.1:p.Gln1948Leu
NP_001035957.1:p.Gln1969Leu
NP_001035957.1:p.Gln1969Leu
LRG_214t1:c.5843A>T
LRG_214t2:c.5906A>T
LRG_214:g.244955A>T
LRG_214p1:p.Gln1948Leu
LRG_214p2:p.Gln1969Leu
NC_000017.10:g.29661949A>T
NM_001042492.2:c.5906A>T
p.Q1969L

Protein change:

Q1948L

Links:

dbSNP: rs143502927

NCBI 1000 Genomes Browser:

rs143502927

Molecular consequence:

NM_000267.3:c.5843A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042492.3:c.5906A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002065258	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004030137	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jul 3, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10678181, 23460398, 29872168, 35264596, 29089047 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002065258

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 3, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004030137

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jul 3, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Nf1 and Gmcsf interact in myeloid leukemogenesis.

Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T, Clapp DW, Shannon KM.

Mol Cell. 2000 Jan;5(1):189-95.

PubMed [citation]

PMID:: 10678181

See all PubMed Citations (6)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002065258.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.5843A>T, in exon 39 that results in an amino acid change, p.Gln1948Leu. This sequence change does not appear to have been previously described in patients with NF1-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.084% in the African/African American subpopulation (dbSNP rs143502927). The p.Gln1948Leu change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. The p.Gln1948Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Gln1948Leu change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004030137.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: NF1 c.5843A>T (p.Gln1948Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251356 control chromosomes, predominantly at a frequency of 0.00074 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although a pseudogene is present, this region does not have high homology to the pseudogene. p. c.5843A>T has been reported in the literature in an individual with Breast cancer (Guindalini_2022) without strong evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27069254, 10678181, 23460398, 29872168, 35264596, 29089047). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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