VCV000135001.14 - ClinVar

NM_016734.3(PAX5):c.638C>T (p.Ser213Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016734.3(PAX5):c.638C>T (p.Ser213Leu)

Variation ID: 135001 Accession: VCV000135001.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.2 9: 36966691 (GRCh38) [ NCBI UCSC ] 9: 36966688 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 9, 2014	Jul 23, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016734.3:c.638C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057953.1:p.Ser213Leu	missense
NM_001280547.2:c.638C>T	NP_001267476.1:p.Ser213Leu	missense
NM_001280548.2:c.638C>T	NP_001267477.1:p.Ser213Leu	missense
NM_001280549.2:c.638C>T	NP_001267478.1:p.Ser213Leu	missense
NM_001280550.2:c.638C>T	NP_001267479.1:p.Ser213Leu	missense
NM_001280551.2:c.314C>T	NP_001267480.1:p.Ser105Leu	missense
NM_001280552.2:c.638C>T	NP_001267481.1:p.Ser213Leu	missense
NM_001280553.2:c.509C>T	NP_001267482.1:p.Ser170Leu	missense
NM_001280554.2:c.509C>T	NP_001267483.1:p.Ser170Leu	missense
NM_001280555.2:c.440C>T	NP_001267484.1:p.Ser147Leu	missense
NM_001280556.2:c.314C>T	NP_001267485.1:p.Ser105Leu	missense
NM_016734.2:c.638C>T
NR_103999.2:n.875C>T		non-coding transcript variant
NR_104000.2:n.875C>T		non-coding transcript variant
NC_000009.12:g.36966691G>A
NC_000009.11:g.36966688G>A
NG_033894.1:g.72789C>T
LRG_1384:g.72789C>T
LRG_1384t1:c.638C>T	LRG_1384p1:p.Ser213Leu
	Q02548:p.Ser213Leu

... more HGVS ... less HGVS

Protein change

S213L, S105L, S147L, S170L

Other names

Canonical SPDI

NC_000009.12:36966690:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00063

Trans-Omics for Precision Medicine (TOPMed) 0.00064

Exome Aggregation Consortium (ExAC) 0.00066

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092

Links

ClinGen: CA161367 UniProtKB: Q02548#VAR_070684 dbSNP: rs137870876 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PAX5		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	157	262

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Uncertain significance (2)	criteria provided, single submitter	Jul 8, 2021	RCV000121768.6
Leukemia, acute lymphoblastic, susceptibility to, 3	Likely benign (1)	criteria provided, single submitter	Feb 11, 2021	RCV001554278.3
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jan 19, 2024	RCV001725978.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jan 19, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002538796.3 First in ClinVar: Jun 24, 2022 Last updated: Jul 23, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24728327) (less)
Likely benign (Feb 11, 2021)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Leukemia, acute lymphoblastic, susceptibility to, 3 Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV001775504.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: The PAX5 c.638C>T (p.Ser213Leu) missense change has a maximum subpopulation frequency of 0.11% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-36966688-G-A?dataset=gnomad_r2_1). This population frequency is higher than expected for … (more) The PAX5 c.638C>T (p.Ser213Leu) missense change has a maximum subpopulation frequency of 0.11% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-36966688-G-A?dataset=gnomad_r2_1). This population frequency is higher than expected for a pathogenic variant in PAX5 causing predisposition to acute lymphoblastic leukemia (BS1). In silico tools are not in agreement about the effect on the gene or protein function and functional studies have not been performed. This variant has been identified in patients without a personal or family history of acute lymphoblastic leukemia (internal data). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1. (less)
Uncertain significance (Jul 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002072301.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the PAX5 gene demonstrated a sequence change, c.638C>T, in exon 6 that results in an amino acid change, p.Ser213Leu. This sequence … (more) DNA sequence analysis of the PAX5 gene demonstrated a sequence change, c.638C>T, in exon 6 that results in an amino acid change, p.Ser213Leu. This sequence change does not appear to have been previously described in patients with PAX5-related disorders and has been described in the gnomAD database with a frequency of 0.11% in the European sub-population (dbSNP rs137870876). The p.Ser213Leu change affects a highly conserved amino acid residue located in a domain of the PAX5 protein that is not known to be functional. The p.Ser213Leu substitution appears to be deleterious 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.Ser213Leu change remains unknown at this time. (less)
Uncertain significance (Mar 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004235715.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely benign (Dec 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003281323.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001962833.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972337.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085966.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24728327)

Comment:

The PAX5 c.638C>T (p.Ser213Leu) missense change has a maximum subpopulation frequency of 0.11% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-36966688-G-A?dataset=gnomad_r2_1). This population frequency is higher than expected for a pathogenic variant in PAX5 causing predisposition to acute lymphoblastic leukemia (BS1). In silico tools are not in agreement about the effect on the gene or protein function and functional studies have not been performed. This variant has been identified in patients without a personal or family history of acute lymphoblastic leukemia (internal data). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1.

Comment:

DNA sequence analysis of the PAX5 gene demonstrated a sequence change, c.638C>T, in exon 6 that results in an amino acid change, p.Ser213Leu. This sequence change does not appear to have been previously described in patients with PAX5-related disorders and has been described in the gnomAD database with a frequency of 0.11% in the European sub-population (dbSNP rs137870876). The p.Ser213Leu change affects a highly conserved amino acid residue located in a domain of the PAX5 protein that is not known to be functional. The p.Ser213Leu substitution appears to be deleterious 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.Ser213Leu change remains unknown at this time.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs137870876 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_016734.3(PAX5):c.638C>T (p.Ser213Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137870876 ...