NM_002834.5(PTPN11):c.333-3T>C AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 26, 2018
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:: RCV000213919.15

Allele description [Variation Report for NM_002834.5(PTPN11):c.333-3T>C]

NM_002834.5(PTPN11):c.333-3T>C

Gene:

PTPN11:protein tyrosine phosphatase non-receptor type 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.13

Genomic location:

Preferred name:

NM_002834.5(PTPN11):c.333-3T>C

HGVS:

NC_000012.12:g.112453192T>C
NG_007459.1:g.39461T>C
NM_001330437.2:c.333-3T>C
NM_001374625.1:c.330-3T>C
NM_002834.4:c.333-3T>C
NM_002834.5:c.333-3T>CMANE SELECT
NM_080601.3:c.333-3T>C
LRG_614t1:c.333-3T>C
LRG_614:g.39461T>C
NC_000012.11:g.112890996T>C
NM_002834.3:c.333-3T>C

Links:

dbSNP: rs146749153

NCBI 1000 Genomes Browser:

rs146749153

Molecular consequence:

NM_001330437.2:c.333-3T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001374625.1:c.330-3T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_002834.5:c.333-3T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_080601.3:c.333-3T>C - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV000272339	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Nov 10, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000920093	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Feb 26, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272339

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Nov 10, 2016)

germline

clinical testing

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

SCV000920093

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Feb 26, 2018)

germline

clinical testing

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	not provided	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272339.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

Variant classified as Uncertain Significance - Favor Benign. The c.333-3T>C vari ant in PTPN11 has identified by our laboratory in 1 mixed ethnicity individual w ith DCM and was also identified in their unaffected parent. It has also been ide ntified in 6/9456 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146749153). This variant is located in the 5' splice region. The Cytosine (C) nucleotide at position 331-3 is consisten t with the consensus splice sequence and computational tools do not suggest an i mpact to splicing. However, this information is not predictive enough to rule ou t pathogenicity. In summary, while the clinical significance of the c.333-3T>C v ariant is uncertain, these data suggest that it is more likely to be benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920093.1

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

Description

Variant summary: PTPN11 c.333-3T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. Two predict this variant creates a cryptic splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 276356 control chromosomes. The observed variant frequency within African control individuals in the gnomAD database is approximately 11.36 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.333-3T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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: Oct 26, 2024

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