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NM_207122.2(EXT2):c.245A>C (p.Asp82Ala) AND Exostoses, multiple, type 2

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 10, 2024
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:
RCV000328182.15

Allele description [Variation Report for NM_207122.2(EXT2):c.245A>C (p.Asp82Ala)]

NM_207122.2(EXT2):c.245A>C (p.Asp82Ala)

Gene:
EXT2:exostosin glycosyltransferase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p11.2
Genomic location:
Preferred name:
NM_207122.2(EXT2):c.245A>C (p.Asp82Ala)
HGVS:
  • NC_000011.10:g.44107957A>C
  • NG_007560.1:g.17409A>C
  • NM_000401.3:c.344A>C
  • NM_001178083.3:c.245A>C
  • NM_001389628.1:c.245A>C
  • NM_001389630.1:c.245A>C
  • NM_207122.2:c.245A>CMANE SELECT
  • NP_000392.3:p.Asp115Ala
  • NP_001171554.1:p.Asp82Ala
  • NP_001376557.1:p.Asp82Ala
  • NP_001376559.1:p.Asp82Ala
  • NP_997005.1:p.Asp82Ala
  • NP_997005.1:p.Asp82Ala
  • LRG_494t1:c.344A>C
  • LRG_494t2:c.245A>C
  • LRG_494:g.17409A>C
  • LRG_494p1:p.Asp115Ala
  • LRG_494p2:p.Asp82Ala
  • NC_000011.9:g.44129507A>C
  • NM_207122.1:c.245A>C
Protein change:
D115A
Links:
dbSNP: rs534539796
NCBI 1000 Genomes Browser:
rs534539796
Molecular consequence:
  • NM_000401.3:c.344A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178083.3:c.245A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001389628.1:c.245A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001389630.1:c.245A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_207122.2:c.245A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Exostoses, multiple, type 2 (EXT2)
Synonyms:
EXOSTOSES, MULTIPLE, TYPE II
Identifiers:
MONDO: MONDO:0007586; MedGen: C1851413; Orphanet: 321; OMIM: 133701

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000371828Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)		Likely benign
(Apr 27, 2017) 		germlineclinical testing

Citation Link,

SCV001380961Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 10, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000371828.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001380961.5

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 82 of the EXT2 protein (p.Asp82Ala). This variant is present in population databases (rs534539796, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 304575). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EXT2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024