NM_001042492.3(NF1):c.6664A>G (p.Thr2222Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 24, 2021
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:: RCV000165324.5

Allele description [Variation Report for NM_001042492.3(NF1):c.6664A>G (p.Thr2222Ala)]

NM_001042492.3(NF1):c.6664A>G (p.Thr2222Ala)

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.6664A>G (p.Thr2222Ala)

HGVS:

NC_000017.11:g.31337840A>G
NG_009018.1:g.247864A>G
NM_000267.3:c.6601A>G
NM_001042492.3:c.6664A>GMANE SELECT
NP_000258.1:p.Thr2201Ala
NP_001035957.1:p.Thr2222Ala
NP_001035957.1:p.Thr2222Ala
LRG_214t1:c.6601A>G
LRG_214t2:c.6664A>G
LRG_214:g.247864A>G
LRG_214p1:p.Thr2201Ala
LRG_214p2:p.Thr2222Ala
NC_000017.10:g.29664858A>G
NM_001042492.2:c.6664A>G
p.T2222A

Protein change:

T2201A

Links:

dbSNP: rs745945481

NCBI 1000 Genomes Browser:

rs745945481

Molecular consequence:

NM_000267.3:c.6601A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001042492.3:c.6664A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000216047	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Uncertain significance (Feb 19, 2016)	germline	clinical testing	Citation Link,
SCV002527662	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely benign (Jul 24, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216047

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (10/2015))

Uncertain significance
(Feb 19, 2016)

germline

clinical testing

Citation Link,

SCV002527662

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely benign
(Jul 24, 2021)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing, curation

Details of each submission

From Ambry Genetics, SCV000216047.4

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

Description

Ã¢â‚¬â€¹<span style="background-color:initial">Thep.T2222A<span style="background-color:initial"> variant (also known as c.6664A>G), located in coding exon 44 of theNF1<span style="background-color:initial"> gene, results from an A to G substitution at nucleotide position 6664. The threonine at codon 2222 is replaced by alanine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFTin silico<span style="background-color:initial"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.T2222A remains unclear.

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

From Sema4, Sema4, SCV002527662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

#	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: Aug 4, 2024

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