VCV000126707.36 - ClinVar

NM_024675.4(PALB2):c.3048del (p.Phe1016fs)

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.

(14)

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/Likely 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.3048del (p.Phe1016fs)

Variation ID: 126707 Accession: VCV000126707.36

Type and length

Deletion, 1 bp

Location

Cytogenetic: 16p12.2 16: 23621427 (GRCh38) [ NCBI UCSC ] 16: 23632748 (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	Apr 19, 2014	Oct 8, 2024	Feb 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.3048del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078951.2:p.Phe1016fs	frameshift
NM_024675.3:c.3048delT
NC_000016.10:g.23621430del
NC_000016.9:g.23632751del
NG_007406.1:g.24931del
LRG_308:g.24931del
LRG_308t1:c.3048del	LRG_308p1:p.Phe1016fs

... more HGVS ... less HGVS

Protein change

F1016fs

Other names

Canonical SPDI

NC_000016.10:23621426:AAAA:AAA

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: CA165090 dbSNP: rs515726104 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	5921	5963

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 (6)	criteria provided, multiple submitters, no conflicts	Feb 24, 2024	RCV000114587.19
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 12, 2022	RCV000129785.13
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 21, 2023	RCV000412897.14
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 9, 2019	RCV001193464.2
Familial cancer of breast Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2021	RCV002477271.1
PALB2-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 11, 2024	RCV004739375.1

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 (Dec 09, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362315.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (4) PubMed: 21932393‚ 25186627‚ 30128536‚ 29486991 Comment: Variant summary: PALB2 c.3048delT (p.Phe1016LeufsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: PALB2 c.3048delT (p.Phe1016LeufsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251448 control chromosomes (gnomAD). c.3048delT has been reported in the literature in individuals affected with breast and/or ovarian cancer (Zheng_2012, Tung_2014, Barrington_2018, Lu_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (Nov 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002067396.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis demonstrated the presence of a heterozygous 1 base-pair deletion in the PALB2 gene, c.3048del. This sequence change results in an amino acid … (more) DNA sequence analysis demonstrated the presence of a heterozygous 1 base-pair deletion in the PALB2 gene, c.3048del. This sequence change results in an amino acid frameshift and creates a premature stop codon 16 amino acids downstream of the mutation, p.Phe1016Leufs*17. This deletion is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PALB2 protein with potentially abnormal function. This sequence change has not been described in population databases (gnomAD, ExAC). The c.3048del sequence change has been identified in an African American woman with breast cancer, and a family history of colorectal cancer, leukemia, and pancreatic cancer (PMID: 21932393). This sequence change is likely causative of susceptibility to breast cancer and pancreatic cancer, however functional studies have not been performed to prove this conclusively. (less)
Pathogenic (Oct 11, 2016)	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: SCV000489479.2 First in ClinVar: Apr 19, 2014 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 27153395‚ 25897114‚ 25428789‚ 25186627‚ 21932393
Pathogenic (Jun 13, 2023)	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: SCV001134549.5 First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024	Publications: PubMed (13) PubMed: 22692731‚ 21932393‚ 25428789‚ 25186627‚ 29625052‚ 32339256‚ 30128536‚ 30287823‚ 29486991‚ 29922827‚ 28888541‚ 27153395‚ 26689913 Comment: The PALB2 c.3048del (p.Phe1016Leufs17) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant … (more) The PALB2 c.3048del (p.Phe1016Leufs17) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32339256 (2020), 30128536 (2019), 30287823 (2018), 29486991 (2018), 28888541 (2017), 27153395 (2016), 25428789 (2015), 25186627 (2015), 21932393 (2012), 22692731 (2012)), head and neck squamous cell carcinoma (PMIDs: 29625052 (2018), 26689913 (2015)), as well as in healthy individuals (PMID: 29922827 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 12, 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: SCV000184594.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 21932393‚ 22692731‚ 25428789‚ 30287823 Comment: The c.3048delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3048, causing … (more) The c.3048delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3048, causing a translational frameshift with a predicted alternate stop codon (p.F1016Lfs*17). This alteration has been reported in an African American woman diagnosed with invasive breast cancer at age 60 who also had a family history of pancreatic cancer (Zheng Y et al. Cancer 2012;118:1362-70). This variant was also reported in an African American woman with triple negative breast cancer diagnosed over the age of 45 (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Feb 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202056.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Nov 21, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490686.6 First in ClinVar: Jan 09, 2017 Last updated: Jul 23, 2024	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 21932393, 25186627, 37169825); This variant is associated with the following publications: (PMID: 28888541, 21932393, 25186627, 25428789, 24870022, 22692731, 29625052, 26689913, 32339256, 30287823, 30128536, 29486991, 36451132, 27153395, 37169825, 29922827) (less)
Pathogenic (Jun 17, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: no Allele origin: germline	Division of Medical Genetics, University of Washington Study: CSER_CHARM Accession: SCV001424809.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020	Comment: This variant leads to a translational frameshift and the introduction of a premature termination codon 17 residues downstream. The variant transcript is predicted to be … (more) This variant leads to a translational frameshift and the introduction of a premature termination codon 17 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PALB2 is a well-established mechanism of disease for increased breast cancer risk (Rahman 2007, Janatova 2013, Antoniou 2014). This variant has an allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with breast cancer (Zheng 2012, Churpek 2015, Tung 2015). Thus, this variant is interpreted as pathogenic. (less) Indication for testing: family history of breast and ovarian cancer
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002778954.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (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: SCV004019636.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Dec 21, 2021)	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: SCV000686004.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 21932393‚ 25428789‚ 27153395‚ 30128536‚ 30287823 Comment: This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21932393, 25428789, 27153395, 30128536, 30287823). In a breast cancer case-control study, this variant was identified in 1/7051 female breast cancer cases and was absent in any controls (PMID: 30287823). This variant has been identified in 1/246228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 21, 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: SCV000633397.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 28492532‚ 17200668‚ 17200671‚ 17200672‚ 24136930‚ 25099575‚ 21932393‚ 25428789 Comment: This sequence change creates a premature translational stop signal (p.Phe1016Leufs17) in the PALB2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Phe1016Leufs17) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs515726104, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21932393, 25428789). ClinVar contains an entry for this variant (Variation ID: 126707). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 11, 2024)	no assertion criteria provided Method: clinical testing	PALB2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005355433.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PALB2 c.3048delT variant is predicted to result in a frameshift and premature protein termination (p.Phe1016Leufs17). This variant has been reported many times in individuals … (more) The PALB2 c.3048delT variant is predicted to result in a frameshift and premature protein termination (p.Phe1016Leufs17). This variant has been reported many times in individuals with breast cancer (see for examples Zheng et al. 2012. PubMed ID: 21932393; Churpek et al. 2015. PubMed ID: 25428789). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PALB2 are expected to be pathogenic and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/126707). This variant is interpreted as pathogenic. (less)
Pathogenic (Feb 28, 2020)	no assertion criteria provided Method: curation	Familial cancer of breast Affected status: no Allele origin: germline	Leiden Open Variation Database Accession: SCV001193333.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (4) PubMed: 21932393‚ 25186627‚ 25428789‚ 30287823 Comment: Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
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Comment:

Variant summary: PALB2 c.3048delT (p.Phe1016LeufsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251448 control chromosomes (gnomAD). c.3048delT has been reported in the literature in individuals affected with breast and/or ovarian cancer (Zheng_2012, Tung_2014, Barrington_2018, Lu_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

DNA sequence analysis demonstrated the presence of a heterozygous 1 base-pair deletion in the PALB2 gene, c.3048del. This sequence change results in an amino acid frameshift and creates a premature stop codon 16 amino acids downstream of the mutation, p.Phe1016Leufs*17. This deletion is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PALB2 protein with potentially abnormal function. This sequence change has not been described in population databases (gnomAD, ExAC). The c.3048del sequence change has been identified in an African American woman with breast cancer, and a family history of colorectal cancer, leukemia, and pancreatic cancer (PMID: 21932393). This sequence change is likely causative of susceptibility to breast cancer and pancreatic cancer, however functional studies have not been performed to prove this conclusively.

Comment:

The PALB2 c.3048del (p.Phe1016Leufs*17) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32339256 (2020), 30128536 (2019), 30287823 (2018), 29486991 (2018), 28888541 (2017), 27153395 (2016), 25428789 (2015), 25186627 (2015), 21932393 (2012), 22692731 (2012)), head and neck squamous cell carcinoma (PMIDs: 29625052 (2018), 26689913 (2015)), as well as in healthy individuals (PMID: 29922827 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

Comment:

The c.3048delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3048, causing a translational frameshift with a predicted alternate stop codon (p.F1016Lfs*17). This alteration has been reported in an African American woman diagnosed with invasive breast cancer at age 60 who also had a family history of pancreatic cancer (Zheng Y et al. Cancer 2012;118:1362-70). This variant was also reported in an African American woman with triple negative breast cancer diagnosed over the age of 45 (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 21932393, 25186627, 37169825); This variant is associated with the following publications: (PMID: 28888541, 21932393, 25186627, 25428789, 24870022, 22692731, 29625052, 26689913, 32339256, 30287823, 30128536, 29486991, 36451132, 27153395, 37169825, 29922827)

Comment:

This variant leads to a translational frameshift and the introduction of a premature termination codon 17 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PALB2 is a well-established mechanism of disease for increased breast cancer risk (Rahman 2007, Janatova 2013, Antoniou 2014). This variant has an allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with breast cancer (Zheng 2012, Churpek 2015, Tung 2015). Thus, this variant is interpreted as pathogenic.

Comment:

This variant deletes 1 nucleotide in exon 10 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21932393, 25428789, 27153395, 30128536, 30287823). In a breast cancer case-control study, this variant was identified in 1/7051 female breast cancer cases and was absent in any controls (PMID: 30287823). This variant has been identified in 1/246228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Phe1016Leufs*17) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs515726104, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21932393, 25428789). ClinVar contains an entry for this variant (Variation ID: 126707). For these reasons, this variant has been classified as Pathogenic.

Comment:

The PALB2 c.3048delT variant is predicted to result in a frameshift and premature protein termination (p.Phe1016Leufs*17). This variant has been reported many times in individuals with breast cancer (see for examples Zheng et al. 2012. PubMed ID: 21932393; Churpek et al. 2015. PubMed ID: 25428789). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PALB2 are expected to be pathogenic and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/126707). This variant is interpreted 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

Title	Author	Journal	Year	Link
Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing.	Zhou J	Cancer	2020	PMID: 32339256
Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing.	Lu HM	JAMA oncology	2019	PMID: 30128536
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.	Momozawa Y	Nature communications	2018	PMID: 30287823
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.	Hu C	JAMA	2018	PMID: 29922827
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
Characteristics of African American women at high-risk for ovarian cancer in the southeast: Results from a Gynecologic Cancer Risk Assessment Clinic.	Barrington DA	Gynecologic oncology	2018	PMID: 29486991
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls.	Lilyquist J	Gynecologic oncology	2017	PMID: 28888541
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes.	Bacolla A	Nucleic acids research	2015	PMID: 25897114
Inherited predisposition to breast cancer among African American women.	Churpek JE	Breast cancer research and treatment	2015	PMID: 25428789
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.	Tung N	Cancer	2015	PMID: 25186627
Breast-cancer risk in families with mutations in PALB2.	Antoniou AC	The New England journal of medicine	2014	PMID: 25099575
The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer.	Janatova M	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2013	PMID: 24136930
Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families.	Catucci I	Familial cancer	2012	PMID: 22692731
Novel germline PALB2 truncating mutations in African American breast cancer patients.	Zheng Y	Cancer	2012	PMID: 21932393
Fanconi anemia is associated with a defect in the BRCA2 partner PALB2.	Xia B	Nature genetics	2007	PMID: 17200672
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.	Reid S	Nature genetics	2007	PMID: 17200671
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.	Rahman N	Nature genetics	2007	PMID: 17200668
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Text-mined citations for rs515726104 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_024675.4(PALB2):c.3048del (p.Phe1016fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs515726104 ...