VCV002674131.2 - ClinVar

NM_024675.4(PALB2):c.1587_1589delinsCC (p.Leu531fs)

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.

(2)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024675.4(PALB2):c.1587_1589delinsCC (p.Leu531fs)

Variation ID: 2674131 Accession: VCV002674131.2

Type and length

Indel, 3 bp

Location

Cytogenetic: 16p12.2 16: 23634957-23634959 (GRCh38) [ NCBI UCSC ] 16: 23646278-23646280 (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 25, 2023	Feb 14, 2024	Sep 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.1587_1589delinsCC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078951.2:p.Leu531fs	frameshift
NM_001407296.1:c.1527_1529delinsCC	NP_001394225.1:p.Leu511fs	frameshift
NM_001407297.1:c.1587_1589delinsCC	NP_001394226.1:p.Leu531fs	frameshift
NM_001407298.1:c.1587_1589delinsCC	NP_001394227.1:p.Leu531fs	frameshift
NM_001407299.1:c.1587_1589delinsCC	NP_001394228.1:p.Leu531fs	frameshift
NM_001407300.1:c.1587_1589delinsCC	NP_001394229.1:p.Leu531fs	frameshift
NM_001407301.1:c.1587_1589delinsCC	NP_001394230.1:p.Leu531fs	frameshift
NM_001407302.1:c.1587_1589delinsCC	NP_001394231.1:p.Leu531fs	frameshift
NM_001407304.1:c.702_704delinsCC	NP_001394233.1:p.Leu236fs	frameshift
NM_001407305.1:c.702_704delinsCC	NP_001394234.1:p.Leu236fs	frameshift
NM_001407306.1:c.702_704delinsCC	NP_001394235.1:p.Leu236fs	frameshift
NM_001407307.1:c.702_704delinsCC	NP_001394236.1:p.Leu236fs	frameshift
NM_001407308.1:c.702_704delinsCC	NP_001394237.1:p.Leu236fs	frameshift
NM_001407309.1:c.702_704delinsCC	NP_001394238.1:p.Leu236fs	frameshift
NM_001407310.1:c.702_704delinsCC	NP_001394239.1:p.Leu236fs	frameshift
NM_001407311.1:c.702_704delinsCC	NP_001394240.1:p.Leu236fs	frameshift
NM_001407312.1:c.-104-4490_-104-4488delinsCC		intron variant
NM_001407313.1:c.-104-4490_-104-4488delinsCC		intron variant
NM_001407314.1:c.49-5684_49-5682delinsCC		intron variant
NC_000016.10:g.23634957_23634959delinsGG
NC_000016.9:g.23646278_23646280delinsGG
NG_007406.1:g.11399_11401delinsCC
LRG_308:g.11399_11401delinsCC
LRG_308t1:c.1587_1589delACTinsCC	LRG_308p1:p.Leu531Cysfs

... more HGVS ... less HGVS

Protein change

L236fs, L511fs, L531fs

Other names

Canonical SPDI

NC_000016.10:23634956:AGT:GG

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

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	5913	5955

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.
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Sep 11, 2023	RCV003452327.1
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2022	RCV003585402.1

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.
Pathogenic (Sep 11, 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: SCV004187463.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Feb 01, 2022)	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: SCV004357917.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This c.1587_1589delinsCC variant creates a frameshift and premature translation stop signal in exon 4 of the PALB2 gene. This variant is expected to result in … (more) This c.1587_1589delinsCC variant creates a frameshift and premature translation stop signal in exon 4 of the PALB2 gene. This variant is expected to result in an absent or non-functional protein product. This variant can also be described as a combination of a Pathogenic frameshift variant c.1592del (p.Leu531Cysfs*30) and a Likely Benign synonymous variant c.1587A>C (p.Pro529=). The c.1592del variant is well described in the literature and known to be disease causing (ClinVar variation ID: 126609). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)

Comment:

This c.1587_1589delinsCC variant creates a frameshift and premature translation stop signal in exon 4 of the PALB2 gene. This variant is expected to result in an absent or non-functional protein product. This variant can also be described as a combination of a Pathogenic frameshift variant c.1592del (p.Leu531Cysfs*30) and a Likely Benign synonymous variant c.1587A>C (p.Pro529=). The c.1592del variant is well described in the literature and known to be disease causing (ClinVar variation ID: 126609). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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 this variant ...

Record last updated Sep 08, 2024

ClinVar Genomic variation as it relates to human health

NM_024675.4(PALB2):c.1587_1589delinsCC (p.Leu531fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...