VCV002762991.5 - ClinVar

NM_024675.4(PALB2):c.48+4C>A

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(2); Likely benign(1)

3 out of 3 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024675.4(PALB2):c.48+4C>A

Variation ID: 2762991 Accession: VCV002762991.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p12.2 16: 23641106 (GRCh38) [ NCBI UCSC ] 16: 23652427 (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	Feb 14, 2024	Feb 23, 2026	Jan 9, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.48+4C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001407296.1:c.48+4C>A		intron variant
NM_001407297.1:c.48+4C>A		intron variant
NM_001407298.1:c.48+4C>A		intron variant
NM_001407299.1:c.48+4C>A		intron variant
NM_001407300.1:c.48+4C>A		intron variant
NM_001407301.1:c.48+4C>A		intron variant
NM_001407302.1:c.48+4C>A		intron variant
NM_001407304.1:c.-1692C>A		5 prime UTR
NM_001407305.1:c.-972+4C>A		intron variant
NM_001407306.1:c.-838+21C>A		intron variant
NM_001407307.1:c.-972+4C>A		intron variant
NM_001407308.1:c.-838+21C>A		intron variant
NM_001407309.1:c.-972+4C>A		intron variant
NM_001407310.1:c.-1692C>A		5 prime UTR
NM_001407311.1:c.-972+4C>A		intron variant
NM_001407312.1:c.-105+4C>A		intron variant
NM_001407313.1:c.-105+4C>A		intron variant
NM_001407314.1:c.48+4C>A		intron variant
NM_024675.3:c.48+4C>A
NC_000016.10:g.23641106G>T
NC_000016.9:g.23652427G>T
NG_007406.1:g.5252C>A
LRG_308:g.5252C>A
LRG_308t1:c.48+4C>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000016.10:23641105:G:T

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: CA2697555740 dbSNP: rs876659843 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		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	6738	6784

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	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Jan 9, 2025	RCV003500287.5
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Dec 23, 2024	RCV005387207.1

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.	Expand all rows Collapse all rows 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 (Dec 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV006045756.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Comment: show The c.48+4C>A intronic variant results from a C to A substitution 4 nucleotides after coding exon 1 in the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, the clinical significance of this variant remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jan 09, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Familial cancer of breast	Myriad Genetics, Inc. Accession: SCV006094350.1 First in ClinVar: Jun 22, 2025 Last updated: Jun 22, 2025	Comment: show This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Sep 23, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Familial cancer of breast	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004327791.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (2) PubMed: 17576681‚ 9536098 Comment: show 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. It affects a nucleotide within the consensus splice site. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The c.48+4C>A intronic variant results from a C to A substitution 4 nucleotides after coding exon 1 in the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, the clinical significance of this variant remains unclear.

Comment:

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. It affects a nucleotide within the consensus splice site.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs876659843 ...

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 Feb 25, 2026