VCV000142756.28 - ClinVar

NM_024675.4(PALB2):c.2507_2509del (p.Val836del)

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.

(10)

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(9); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024675.4(PALB2):c.2507_2509del (p.Val836del)

Variation ID: 142756 Accession: VCV000142756.28

Type and length

Deletion, 3 bp

Location

Cytogenetic: 16p12.2 16: 23629645-23629647 (GRCh38) [ NCBI UCSC ] 16: 23640966-23640968 (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	Dec 6, 2016	Jul 23, 2024	May 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.2507_2509del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078951.2:p.Val836del	inframe deletion
NM_024675.3:c.2507_2509delTCG
NC_000016.10:g.23629647_23629649del
NC_000016.9:g.23640968_23640970del
NG_007406.1:g.16711_16713del
LRG_308:g.16711_16713del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000016.10:23629644:CGACG:CG

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.

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

Links

ClinGen: CA169333 dbSNP: rs587782697 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.
PALB2		-	-	GRCh38 GRCh37	5910	5952

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 10, 2023	RCV000132137.17
Fanconi anemia	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000354505.6
Familial cancer of breast	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 13, 2024	RCV000465007.16
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 13, 2024	RCV000656935.8

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 (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Fanconi Anemia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000396092.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Observation 1: Observation 2:
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	PALB2-Related Cancer Susceptibility Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000396093.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Observation 1: Observation 2:
Uncertain significance (Feb 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005053894.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000550625.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This variant, c.2507_2509del, results in the deletion of 1 amino acid(s) of the PALB2 protein (p.Val836del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.2507_2509del, results in the deletion of 1 amino acid(s) of the PALB2 protein (p.Val836del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782697, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142756). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. (less)
Uncertain significance (Dec 05, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000187208.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: The c.2507_2509delTCG variant (also known as p.V836del) is located in coding exon 5 of the PALB2 gene. This variant results from an in-frame TCG deletion … (more) The c.2507_2509delTCG variant (also known as p.V836del) is located in coding exon 5 of the PALB2 gene. This variant results from an in-frame TCG deletion at nucleotide positions 2507 to 2509. This results in the in-frame deletion of a valine at codon 836. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Feb 16, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000784949.2 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018
Uncertain significance (Jul 16, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601763.2 First in ClinVar: Sep 28, 2017 Last updated: Jan 26, 2021
Likely benign (Mar 31, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004019690.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (1) PubMed: 25085752 Comment: This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more) This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
Uncertain significance (Jan 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000903544.3 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Comment: This variant deletes a single amino acid from the PALB2 protein. To our knowledge, functional studies have not been reported for this variant. This variant … (more) This variant deletes a single amino acid from the PALB2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (May 13, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292658.15 First in ClinVar: Jul 24, 2016 Last updated: Jul 23, 2024	Comment: In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published … (more) In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28825729, 24485656, 19609323) (less)

Comment:

This variant, c.2507_2509del, results in the deletion of 1 amino acid(s) of the PALB2 protein (p.Val836del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782697, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142756). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Comment:

The c.2507_2509delTCG variant (also known as p.V836del) is located in coding exon 5 of the PALB2 gene. This variant results from an in-frame TCG deletion at nucleotide positions 2507 to 2509. This results in the in-frame deletion of a valine at codon 836. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This variant deletes a single amino acid from the PALB2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28825729, 24485656, 19609323)

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

Title	Author	Journal	Year	Link
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.	Pruss D	Breast cancer research and treatment	2014	PMID: 25085752

Text-mined citations for rs587782697 ...

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_024675.4(PALB2):c.2507_2509del (p.Val836del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587782697 ...