VCV000126757.109 - ClinVar

NM_024675.4(PALB2):c.509_510del (p.Arg170fs)

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.

(46)

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.509_510del (p.Arg170fs)

Variation ID: 126757 Accession: VCV000126757.109

Type and length

Deletion, 2 bp

Location

Cytogenetic: 16p12.2 16: 23636036-23636037 (GRCh38) [ NCBI UCSC ] 16: 23647357-23647358 (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 20, 2024	Sep 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.509_510del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078951.2:p.Arg170fs	frameshift
NM_024675.4:c.509_510delGA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024675.3:c.509_510delGA
NC_000016.10:g.23636037_23636038del
NC_000016.9:g.23647358_23647359del
NG_007406.1:g.10321_10322del
LRG_308:g.10321_10322del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000016.10:23636035:TCT:T

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: CA214889 dbSNP: rs515726123 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 (11)	criteria provided, multiple submitters, no conflicts	Sep 16, 2024	RCV000114645.40
Hereditary cancer-predisposing syndrome	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 6, 2023	RCV000130658.26
not provided	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Dec 15, 2023	RCV000212776.49
not specified	Pathogenic (1)	criteria provided, single submitter	Jul 23, 2018	RCV001000478.11
Malignant tumor of breast	Pathogenic (2)	criteria provided, single submitter	May 11, 2021	RCV001356172.7
Carcinoma of pancreas	Pathogenic (1)	no assertion criteria provided	Mar 4, 2021	RCV001391207.5
Breast and/or ovarian cancer	Pathogenic (2)	criteria provided, single submitter	May 26, 2022	RCV001270995.7
Breast cancer, susceptibility to Pancreatic cancer, susceptibility to, 3	Pathogenic (1)	criteria provided, single submitter	Feb 5, 2019	RCV001258079.5
Fanconi anemia complementation group N	Pathogenic (1)	criteria provided, single submitter	Jun 5, 2019	RCV003137629.6
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	May 22, 2024	RCV003322596.3
Breast-ovarian cancer, familial, susceptibility to, 5	Pathogenic (1)	criteria provided, single submitter	Feb 28, 2024	RCV004562253.1
Familial cancer of breast Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3	Pathogenic (1)	criteria provided, single submitter	Mar 16, 2022	RCV002505027.4
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	no assertion criteria provided	Aug 26, 2022	RCV003155916.4
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 9, 2021	RCV001554297.5
PALB2-related disorder	Pathogenic (2)	criteria provided, single submitter	Apr 27, 2017	RCV004528797.2
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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 (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266111.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 40-49 years
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	PALB2-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000396132.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (6) PubMed: 20582465‚ 20412113‚ 21285249‚ 24061862‚ 20122277‚ 21165770 Comment: The PALB2 c.509_510delGA (p.Arg170IlefsTer14) variant results in frameshift and is predicted to result in premature truncation of the protein. The p.Arg170IlefsTer14 variant is reported in … (more) The PALB2 c.509_510delGA (p.Arg170IlefsTer14) variant results in frameshift and is predicted to result in premature truncation of the protein. The p.Arg170IlefsTer14 variant is reported in at least six studies in which it is found in a heterozygous state in a total of 23 breast cancer patients, two ovarian cancer patients and one pancreatic cancer patient (Dansonka-Mieszkowska et al. 2010; Slater et al. 2010; Casadei et al. 2011; Bogdanova et al. 2011; Adank et al. 2011; Noskowicz et al. 2014). This variant has not been reported in individuals with Fanconi anemia. The p.Arg170IlefsTer14 variant was found in a heterozygous state in one of 5097 controls and is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant creates a premature stop codon which shortens the PALB2 protein to 182 amino acids from 1186 amino acids. This removes the C-terminal domain which contains the WD40 repeats necessary for BRCA2/PALB2 complex formation. Other deletion variants that remove the C-terminal domain of the PALB2 protein have been shown to have highly reduced BRCA2 binding capacity and be defective in the repair of ds breaks and mitomyocin C-induced damages. To date, all PALB2 variants detected in families with breast cancer or Fanconi anemia have been frameshift or nonsense changes leading to a truncated protein. Based on the evidence and the potential impact of frameshift variants, the p.Arg170IlefsTer14 variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499704.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Jun 15, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000211483.14 First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019	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; Observed … (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; Observed in individuals with breast and pancreatic cancers and is a recurrent pathogenic variant in Central and Eastern European populations (Dansonka-Mieszkowska 2010, Slater 2010, Casadei 2011, Noskowicz 2014, Cybulski 2015, Wojcik 2016, Kluska 2017, Hilz 2019); Case control studies suggest this variant is associated with breast cancer (Cybulski 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28407996, 26720728, 23935381, 20122277, 20412113, 21285249, 26843898, 24061862, 27038244, 28279176, 28709830, 27488870, 27757719, 27624329, 27099641, 27106063, 25330149, 26270727, 20582465, 28158555, 25959805, 29478780, 29052111, 30086788, 30833416, 31159747, 30113427, 31312277, 31570822, 29625052, 26689913, 32885271, 32554798) (less)
Pathogenic (Jul 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581286.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4, PM2_SUP, PP1	Number of individuals with the variant: 2 Sex: male
Pathogenic (Nov 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV002819235.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023
Pathogenic (May 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838091.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Pathogenic (Feb 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 5 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005049735.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202053.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004027654.2 First in ClinVar: Aug 26, 2023 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4 Clinical Features: Family history of cancer (present) Sex: female
Pathogenic (Sep 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428835.6 First in ClinVar: Aug 15, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4 Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Jul 23, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157357.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: The PALB2 c.509_510delGA; p.Arg170fs variant (rs515726124) is a recurrent alteration in individuals with breast cancer (Casadel 2011, Cybulski 2015, Cybulski 2015b, Dansonka-Mieszkowska 2010, Kluska 2017, … (more) The PALB2 c.509_510delGA; p.Arg170fs variant (rs515726124) is a recurrent alteration in individuals with breast cancer (Casadel 2011, Cybulski 2015, Cybulski 2015b, Dansonka-Mieszkowska 2010, Kluska 2017, Noskowicz 2014), and is significantly enriched in affected individuals compared to the healthy population (Cybulski 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 126757), and found in the general population with a low overall allele frequency of 0.003% (8/246222 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Casadel S et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011; 71(6):2222-9. Cybulski C et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015; 16(6):638-44. Cybulski C et al. Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. Clin Genet. 2015b; 88(4):366-70. Dansonka-Mieszkowska A et al. A novel germline PALB2 deletion in Polish breast and ovarian cancer patients. BMC Med Genet. 2010; 11:20. Kluska A et al. PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. BMC Med Genomics. 2017; 10(1):14. Noskowicz M et al. Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe. Fam Cancer. 2014; 13(2):137-42. (less)
Pathogenic (May 11, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Malignant tumor of breast Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001623425.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Publications: PubMed (6) PubMed: 20122277‚ 21285249‚ 27106063‚ 25959805‚ 24061862‚ 28158555 Comment: Variant summary: PALB2 c.509_510delGA (p.Arg170IlefsX14) 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.509_510delGA (p.Arg170IlefsX14) 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 allele was found at a frequency of 6.1e-05 in 260850 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in PALB2 causing Breast Cancer (6.1e-05 vs 0.00016), allowing no conclusion about variant significance. c.509_510delGA has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer and pancreatic cancer (e.g. Dansonka-Mieszkowska_2010, Casadei_2011, Noskowicz_2014, Cybulski_2015, Borecka_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant impairs DNA binding ability, fails to stimulate RAD51 and fails to localize to DNA damage sites (Pauty_2017). Nineteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Nov 21, 2017)	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: SCV002066911.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 13 amino acids downstream of the mutation, p.Arg170Ilefs14. This … (more) This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 13 amino acids downstream of the mutation, p.Arg170Ilefs14. This pathogenic sequence change 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 pathogenic sequence change has previously been described in patients with PALB2-related breast, ovarian and pancreatic cancers (Dansonka-Mieszkowska et al. 2010; Slater et al. 2010; Casadei et al. 2011; Bogdanova et al. 2011; Adank et al. 2011; Noskowicz et al. 2014; Kluska et al. 2017). Additionally, a breast cancer patient with t-MN was reported to have a different pathogenic PALB2 mutation (Churpek et al. 2016). This pathogenic sequence change may be the germline predisposition to this patient's therapy-related myeloid neoplasm (t-NM), however functional studies have not been performed to prove this conclusively. Compound heterozygous pathogenic variants in PALB2 have been associated with Fanconi anemia of complementation group N [OMIM#610832]. Heterozygous pathogenic variants in PALB2 have been associated with increased susceptibility to cancers including breast cancer [OMIM#114480] and pancreatic cancer [OMIM#613348]. (less)
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000839054.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Nov 02, 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: SCV000489643.2 First in ClinVar: Jan 01, 2016 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 20122277
Pathogenic (Mar 16, 2022)	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: SCV002811714.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial cancer of breast Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366810.4 First in ClinVar: Jul 06, 2020 Last updated: Feb 25, 2023	Comment: PVS1, PS3, PS4_STR
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010955.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
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: SCV004019227.1 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 (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004024286.2 First in ClinVar: Aug 13, 2023 Last updated: Aug 18, 2023
Pathogenic (Aug 20, 2021)	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: SCV000601792.5 First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024	Publications: PubMed (37) PubMed: 20122277‚ 20412113‚ 21285249‚ 24061862‚ 25959805‚ 25330149‚ 28279176‚ 28158555‚ 27106063‚ 27038244‚ 26720728‚ 26270727‚ 26083025‚ 25452441‚ 25186627‚ 25099575‚ 24415441‚ 24136930‚ 21165770‚ 20582465‚ 26689913‚ 28709830‚ 29052111‚ 29478780‚ 29625052‚ 30086788‚ 30113427‚ 30833416‚ 31159747‚ 31312277‚ 31570822‚ 32546565‚ 32554798‚ 32853339‚ 32885271‚ 32997802‚ 33674644 Comment: This frameshift variant causes the premature termination of PALB2 protein synthesis. In addition, it has been identified in individuals with breast, ovarian and pancreatic cancers … (more) This frameshift variant causes the premature termination of PALB2 protein synthesis. In addition, it has been identified in individuals with breast, ovarian and pancreatic cancers as well as in healthy controls in the published literature (PMID: 28279176 (2017), 27106063 (2016), 27038244 (2016), 26720728 (2016), 26270727 (2015), 26083025 (2015), 25959805 (2015), 25452441 (2015), 25330149 (2015), 25186627 (2015), 25099575 (2014), 24415441 (2014), 24136930 (2013), 24061862 (2014), 21285249 (2011), 21165770 (2011), 20582465 (2011), 20412113 (2010), 20122277 (2010)). Functional studies in the published literature report this variant reduced DNA binding and failed to stimulate RAD51-mediated strand invasion (PMID: 28158555 (2017)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jun 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group N Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003822348.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Mar 06, 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: SCV000686065.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 20122277‚ 20412113‚ 20582465‚ 21285249‚ 24061862‚ 24136930‚ 25099575‚ 25186627‚ 26270727‚ 27106063‚ 28158555‚ 33471991 Comment: This variant deletes 2 nucleotides in exon 4 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 2 nucleotides in exon 4 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. A functional study reported that this variant impacts PALB2 binding to DNA (PMID: 28158555). This variant has been detected in over 40 individuals affected with breast, ovarian and pancreatic cancer (PMID: 20122277, 20412113, 20582465, 21285249, 24136930, 24061862, 25099575, 25186627, 26270727, 27106063, 33471991; Leiden Open Variation Database DB-ID PALB2_010036). This variant has been identified in 9/251446 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 28, 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: SCV000166665.12 First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024	Publications: PubMed (15) PubMed: 28492532‚ 17200668‚ 17200671‚ 17200672‚ 24136930‚ 25099575‚ 20122277‚ 20412113‚ 21285249‚ 24061862‚ 25330149‚ 25959805‚ 26083025‚ 27038244‚ 27106063 Comment: This sequence change creates a premature translational stop signal (p.Arg170Ilefs14) 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.Arg170Ilefs14) 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 (rs515726124, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and pancreatic cancer (PMID: 20122277, 20412113, 21285249, 24061862, 25330149, 25959805, 26083025, 27038244, 27106063). ClinVar contains an entry for this variant (Variation ID: 126757). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848651.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (6) PubMed: 20122277‚ 28279176‚ 25330149‚ 24061862‚ 20412113‚ 21285249 Comment: The p.Arg170IlefsX14 variant in PALB2 has been reported in numerous individuals with PABL2-associated cancers, including familial breast, ovarian, and pancreatic cancer and is considered to … (more) The p.Arg170IlefsX14 variant in PALB2 has been reported in numerous individuals with PABL2-associated cancers, including familial breast, ovarian, and pancreatic cancer and is considered to be a founder variant of central and eastern European origin (selected references: Dansonka-Mieszkowska 2010 PMID: 20122277, Slater 2010 PMID: 20412113, Casadei 2011 PMID: 21285249, Noskowicz 2014 PMID: 24061862, Cybulski 2015 PMID: 25330149, Kluska 2017 PMID: 28279176). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 126757) and has been identified in 0.001% (2/68010) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 170 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PALB2 gene is an established disease mechanism in PALB2-associated cancers, including autosomal dominant breast cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PALB2-associated cancers. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting. (less)
Pathogenic (Oct 26, 2021)	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: SCV000185544.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (16) PubMed: 20122277‚ 20412113‚ 20582465‚ 21165770‚ 21285249‚ 21365267‚ 24061862‚ 25330149‚ 25959805‚ 26270727‚ 26720728‚ 27038244‚ 27099641‚ 27106063‚ 28158555‚ 28279176 Comment: The c.509_510delGA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 509 to … (more) The c.509_510delGA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 509 to 510, causing a translational frameshift with a predicted alternate stop codon (p.R170Ifs*14). This alteration has been reported in familial breast, ovarian, and pancreatic cancer cohorts with carrier ethnicity data supporting c.509_510delGA as a founder mutation of central European origin (Dansonka-Mieszkowska A et al. BMC Med. Genet. 2010 Feb;11:20; Slater EP et al. Clin. Genet. 2010 Nov;78:490-4; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Noskowicz M et al. Fam. Cancer. 2014 Jun;13:137-42; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51; Kluska A et al. BMC Med. Genomics. 2017 Mar;10:14). Additional data has led authors to suggest that this is one of two PALB2 founder mutations associated with poor outcome in Polish breast cancer patients (Cybulski C et al. Lancet Oncol. 2015 Jun;16:638-44). Further, a functional characterization of this alteration showed that the truncated protein results in weakly bound DNA substrates, suggesting that the loss of the second DNA binding domain affects the affinity for DNA, resulting in significantly impaired DNA binding (Pauty J et al. Nucleic Acids Res. 2017 Mar;45:2644-2657). 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 (Dec 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199041.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (May 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247809.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821754.2 First in ClinVar: Oct 10, 2018 Last updated: May 04, 2020	Comment: This mutation is a 2 bp deletion at codon 509 of the PALB2 gene. It results in a frame-shift creating new stop codon 14 amino … (more) This mutation is a 2 bp deletion at codon 509 of the PALB2 gene. It results in a frame-shift creating new stop codon 14 amino acid residues later, thus resulting in absent or disrupted protein product. Truncating variants in PALB2 are known to be pathogenic. This particular truncation has been reported in the literature in association with familial breast and pancreatic cancers (PMID: 20412113; PMID: 21285249). The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126757). (less)
Pathogenic (Feb 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Susceptibility to breast cancer Pancreatic cancer susceptibility 3 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434918.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: This c.509_510delGA (p.Arg170Ilefs14) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated … (more) This c.509_510delGA (p.Arg170Ilefs14) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated patients affected with breast cancer (PMID 21285249, 24061862, 25330149, 26083025), ovarian cancer (PMID 21285249) and pancreatic cancer (PMID 27106063) and is extremely rare in general population. Therefore, the c.509_510delGA (p.Arg170Ilefs*14) variant in the PALB2 gene is classified as pathogenic. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447492.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001551263.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The PALB2 p.Arg170Ilefs14 variant was identified in 40 of 17778 proband chromosomes (frequency: 0.002) from American and Central European individuals or families with breast/ovarian cancer, … (more) The PALB2 p.Arg170Ilefs14 variant was identified in 40 of 17778 proband chromosomes (frequency: 0.002) from American and Central European individuals or families with breast/ovarian cancer, colon or familial pancreatic cancer and was identified in 1 of 13574 control chromosomes (freq: 0.00007) from healthy individuals (Antoniou 2014 , AlDubayan 2018, Bogdanova 2011, Cybulski 2015, Dansonka-Mieszkowska 2010, Kluska 2017, Noskowicz 2014, Slater 2010). The variant was identified in dbSNP (ID: rs515726124) as "With Pathogenic allele", in ClinVar (classified pathogenic by GeneDx, Invitae, Ambry Genetics and 9 other submitters), and LOVD 3.0 (1x) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.509_510del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 170 and leads to a premature stop codon 14 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 associated breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001905844.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	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: SCV001980275.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Feb 28, 2020)	no assertion criteria provided Method: curation	not provided Affected status: no Allele origin: germline	Leiden Open Variation Database Accession: SCV001192985.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (12) PubMed: 20122277‚ 20412113‚ 20589654‚ 21165770‚ 21285249‚ 24061862‚ 24136930‚ 24415441‚ 25099575‚ 25186627‚ 25330149‚ 25452441 Comment: Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.
Pathogenic (Jun 11, 2019)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001451807.1 First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020	Publications: PubMed (1) PubMed: 32295079 Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Mar 04, 2021)	no assertion criteria provided Method: case-control	Carcinoma of pancreas Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001593123.1 First in ClinVar: May 14, 2021 Last updated: May 14, 2021	Number of individuals with the variant: 2 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Aug 09, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001774881.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Indication for testing: breast cancer Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808997.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	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: SCV001741257.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (May 02, 2022)	no assertion criteria provided Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002583447.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588984.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	PALB2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004116745.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The PALB2 c.509_510delGA variant is predicted to result in a frameshift and premature protein termination (p.Arg170Ilefs14). This variant has been reported in multiple unrelated individuals … (more) The PALB2 c.509_510delGA variant is predicted to result in a frameshift and premature protein termination (p.Arg170Ilefs14). This variant has been reported in multiple unrelated individuals with breast and/or ovarian cancer (see for example - Dansonka-Mieszkowska et al. 2010. PubMed ID: 20122277; Casadei et al. 2011. PubMed ID: 21285249; Cybulski et al. 2015. PubMed ID: 25330149). This variant is reported in 0.0070% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126757/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Nov 06, 2014)	no assertion criteria provided Method: clinical testing	Breast carcinoma Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000207352.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Publications: PubMed (3) PubMed: 20122277‚ 20412113‚ 21285249
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953087.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

The PALB2 c.509_510delGA (p.Arg170IlefsTer14) variant results in frameshift and is predicted to result in premature truncation of the protein. The p.Arg170IlefsTer14 variant is reported in at least six studies in which it is found in a heterozygous state in a total of 23 breast cancer patients, two ovarian cancer patients and one pancreatic cancer patient (Dansonka-Mieszkowska et al. 2010; Slater et al. 2010; Casadei et al. 2011; Bogdanova et al. 2011; Adank et al. 2011; Noskowicz et al. 2014). This variant has not been reported in individuals with Fanconi anemia. The p.Arg170IlefsTer14 variant was found in a heterozygous state in one of 5097 controls and is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant creates a premature stop codon which shortens the PALB2 protein to 182 amino acids from 1186 amino acids. This removes the C-terminal domain which contains the WD40 repeats necessary for BRCA2/PALB2 complex formation. Other deletion variants that remove the C-terminal domain of the PALB2 protein have been shown to have highly reduced BRCA2 binding capacity and be defective in the repair of ds breaks and mitomyocin C-induced damages. To date, all PALB2 variants detected in families with breast cancer or Fanconi anemia have been frameshift or nonsense changes leading to a truncated protein. Based on the evidence and the potential impact of frameshift variants, the p.Arg170IlefsTer14 variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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; Observed in individuals with breast and pancreatic cancers and is a recurrent pathogenic variant in Central and Eastern European populations (Dansonka-Mieszkowska 2010, Slater 2010, Casadei 2011, Noskowicz 2014, Cybulski 2015, Wojcik 2016, Kluska 2017, Hilz 2019); Case control studies suggest this variant is associated with breast cancer (Cybulski 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28407996, 26720728, 23935381, 20122277, 20412113, 21285249, 26843898, 24061862, 27038244, 28279176, 28709830, 27488870, 27757719, 27624329, 27099641, 27106063, 25330149, 26270727, 20582465, 28158555, 25959805, 29478780, 29052111, 30086788, 30833416, 31159747, 30113427, 31312277, 31570822, 29625052, 26689913, 32885271, 32554798)

Comment:

The PALB2 c.509_510delGA; p.Arg170fs variant (rs515726124) is a recurrent alteration in individuals with breast cancer (Casadel 2011, Cybulski 2015, Cybulski 2015b, Dansonka-Mieszkowska 2010, Kluska 2017, Noskowicz 2014), and is significantly enriched in affected individuals compared to the healthy population (Cybulski 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 126757), and found in the general population with a low overall allele frequency of 0.003% (8/246222 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Casadel S et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011; 71(6):2222-9. Cybulski C et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015; 16(6):638-44. Cybulski C et al. Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. Clin Genet. 2015b; 88(4):366-70. Dansonka-Mieszkowska A et al. A novel germline PALB2 deletion in Polish breast and ovarian cancer patients. BMC Med Genet. 2010; 11:20. Kluska A et al. PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. BMC Med Genomics. 2017; 10(1):14. Noskowicz M et al. Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe. Fam Cancer. 2014; 13(2):137-42.

Comment:

Variant summary: PALB2 c.509_510delGA (p.Arg170IlefsX14) 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 allele was found at a frequency of 6.1e-05 in 260850 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in PALB2 causing Breast Cancer (6.1e-05 vs 0.00016), allowing no conclusion about variant significance. c.509_510delGA has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer and pancreatic cancer (e.g. Dansonka-Mieszkowska_2010, Casadei_2011, Noskowicz_2014, Cybulski_2015, Borecka_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant impairs DNA binding ability, fails to stimulate RAD51 and fails to localize to DNA damage sites (Pauty_2017). Nineteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 13 amino acids downstream of the mutation, p.Arg170Ilefs*14. This pathogenic sequence change 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 pathogenic sequence change has previously been described in patients with PALB2-related breast, ovarian and pancreatic cancers (Dansonka-Mieszkowska et al. 2010; Slater et al. 2010; Casadei et al. 2011; Bogdanova et al. 2011; Adank et al. 2011; Noskowicz et al. 2014; Kluska et al. 2017). Additionally, a breast cancer patient with t-MN was reported to have a different pathogenic PALB2 mutation (Churpek et al. 2016). This pathogenic sequence change may be the germline predisposition to this patient's therapy-related myeloid neoplasm (t-NM), however functional studies have not been performed to prove this conclusively. Compound heterozygous pathogenic variants in PALB2 have been associated with Fanconi anemia of complementation group N [OMIM#610832]. Heterozygous pathogenic variants in PALB2 have been associated with increased susceptibility to cancers including breast cancer [OMIM#114480] and pancreatic cancer [OMIM#613348].

Comment:

This frameshift variant causes the premature termination of PALB2 protein synthesis. In addition, it has been identified in individuals with breast, ovarian and pancreatic cancers as well as in healthy controls in the published literature (PMID: 28279176 (2017), 27106063 (2016), 27038244 (2016), 26720728 (2016), 26270727 (2015), 26083025 (2015), 25959805 (2015), 25452441 (2015), 25330149 (2015), 25186627 (2015), 25099575 (2014), 24415441 (2014), 24136930 (2013), 24061862 (2014), 21285249 (2011), 21165770 (2011), 20582465 (2011), 20412113 (2010), 20122277 (2010)). Functional studies in the published literature report this variant reduced DNA binding and failed to stimulate RAD51-mediated strand invasion (PMID: 28158555 (2017)). Based on the available information, this variant is classified as pathogenic.

Comment:

This variant deletes 2 nucleotides in exon 4 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. A functional study reported that this variant impacts PALB2 binding to DNA (PMID: 28158555). This variant has been detected in over 40 individuals affected with breast, ovarian and pancreatic cancer (PMID: 20122277, 20412113, 20582465, 21285249, 24136930, 24061862, 25099575, 25186627, 26270727, 27106063, 33471991; Leiden Open Variation Database DB-ID PALB2_010036). This variant has been identified in 9/251446 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.Arg170Ilefs*14) 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 (rs515726124, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and pancreatic cancer (PMID: 20122277, 20412113, 21285249, 24061862, 25330149, 25959805, 26083025, 27038244, 27106063). ClinVar contains an entry for this variant (Variation ID: 126757). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Arg170IlefsX14 variant in PALB2 has been reported in numerous individuals with PABL2-associated cancers, including familial breast, ovarian, and pancreatic cancer and is considered to be a founder variant of central and eastern European origin (selected references: Dansonka-Mieszkowska 2010 PMID: 20122277, Slater 2010 PMID: 20412113, Casadei 2011 PMID: 21285249, Noskowicz 2014 PMID: 24061862, Cybulski 2015 PMID: 25330149, Kluska 2017 PMID: 28279176). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 126757) and has been identified in 0.001% (2/68010) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 170 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PALB2 gene is an established disease mechanism in PALB2-associated cancers, including autosomal dominant breast cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PALB2-associated cancers. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting.

Comment:

The c.509_510delGA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 509 to 510, causing a translational frameshift with a predicted alternate stop codon (p.R170Ifs*14). This alteration has been reported in familial breast, ovarian, and pancreatic cancer cohorts with carrier ethnicity data supporting c.509_510delGA as a founder mutation of central European origin (Dansonka-Mieszkowska A et al. BMC Med. Genet. 2010 Feb;11:20; Slater EP et al. Clin. Genet. 2010 Nov;78:490-4; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Noskowicz M et al. Fam. Cancer. 2014 Jun;13:137-42; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51; Kluska A et al. BMC Med. Genomics. 2017 Mar;10:14). Additional data has led authors to suggest that this is one of two PALB2 founder mutations associated with poor outcome in Polish breast cancer patients (Cybulski C et al. Lancet Oncol. 2015 Jun;16:638-44). Further, a functional characterization of this alteration showed that the truncated protein results in weakly bound DNA substrates, suggesting that the loss of the second DNA binding domain affects the affinity for DNA, resulting in significantly impaired DNA binding (Pauty J et al. Nucleic Acids Res. 2017 Mar;45:2644-2657). 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:

This mutation is a 2 bp deletion at codon 509 of the PALB2 gene. It results in a frame-shift creating new stop codon 14 amino acid residues later, thus resulting in absent or disrupted protein product. Truncating variants in PALB2 are known to be pathogenic. This particular truncation has been reported in the literature in association with familial breast and pancreatic cancers (PMID: 20412113; PMID: 21285249). The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126757).

Comment:

This c.509_510delGA (p.Arg170Ilefs*14) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated patients affected with breast cancer (PMID 21285249, 24061862, 25330149, 26083025), ovarian cancer (PMID 21285249) and pancreatic cancer (PMID 27106063) and is extremely rare in general population. Therefore, the c.509_510delGA (p.Arg170Ilefs*14) variant in the PALB2 gene is classified as pathogenic.

Comment:

The PALB2 p.Arg170Ilefs*14 variant was identified in 40 of 17778 proband chromosomes (frequency: 0.002) from American and Central European individuals or families with breast/ovarian cancer, colon or familial pancreatic cancer and was identified in 1 of 13574 control chromosomes (freq: 0.00007) from healthy individuals (Antoniou 2014 , AlDubayan 2018, Bogdanova 2011, Cybulski 2015, Dansonka-Mieszkowska 2010, Kluska 2017, Noskowicz 2014, Slater 2010). The variant was identified in dbSNP (ID: rs515726124) as "With Pathogenic allele", in ClinVar (classified pathogenic by GeneDx, Invitae, Ambry Genetics and 9 other submitters), and LOVD 3.0 (1x) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.509_510del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 170 and leads to a premature stop codon 14 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2 associated breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

The PALB2 c.509_510delGA variant is predicted to result in a frameshift and premature protein termination (p.Arg170Ilefs*14). This variant has been reported in multiple unrelated individuals with breast and/or ovarian cancer (see for example - Dansonka-Mieszkowska et al. 2010. PubMed ID: 20122277; Casadei et al. 2011. PubMed ID: 21285249; Cybulski et al. 2015. PubMed ID: 25330149). This variant is reported in 0.0070% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126757/). Frameshift variants in PALB2 are expected to be pathogenic. 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
Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients.	von Stedingk K	Scientific reports	2021	PMID: 33674644
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Frequency and molecular characteristics of PALB2-associated cancers in Russian patients.	Preobrazhenskaya EV	International journal of cancer	2021	PMID: 32997802
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.	Lerner-Ellis J	Journal of cancer research and clinical oncology	2021	PMID: 32885271
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.	Darst BF	Journal of the National Cancer Institute	2021	PMID: 32853339
Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.	Song H	Journal of medical genetics	2021	PMID: 32546565
A germline PALB2 pathogenic variant identified in a pediatric high-grade glioma.	Zhong Y	Cold Spring Harbor molecular case studies	2020	PMID: 32554798
Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study.	Staaf J	Nature medicine	2019	PMID: 31570822
Allelic variants of breast cancer susceptibility genes PALB2 and RECQL in the Latvian population.	Hilz P	Hereditary cancer in clinical practice	2019	PMID: 31312277
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance.	Horak P	Cold Spring Harbor molecular case studies	2019	PMID: 30833416
Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts.	Zhan W	Pancreas	2018	PMID: 30113427
Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity.	Penkert J	Breast cancer research : BCR	2018	PMID: 30086788
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
Inherited DNA-Repair Defects in Colorectal Cancer.	AlDubayan SH	American journal of human genetics	2018	PMID: 29478780
Targeted massively parallel sequencing characterises the mutation spectrum of PALB2 in breast and ovarian cancer cases from Poland and Ukraine.	Myszka A	Familial cancer	2018	PMID: 29052111
Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2.	Schoolmeester JK	Human pathology	2017	PMID: 28709830
PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.	Kluska A	BMC medical genomics	2017	PMID: 28279176
Cancer-causing mutations in the tumor suppressor PALB2 reveal a novel cancer mechanism using a hidden nuclear export signal in the WD40 repeat motif.	Pauty J	Nucleic acids research	2017	PMID: 28158555
Mutation analysis of the PALB2 gene in unselected pancreatic cancer patients in the Czech Republic.	Borecka M	Cancer genetics	2016	PMID: 27106063
PALB2: research reaching to clinical outcomes for women with breast cancer.	Southey MC	Hereditary cancer in clinical practice	2016	PMID: 27099641
Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?	Lener MR	International journal of cancer	2016	PMID: 27038244
Inherited Mutations in Women With Ovarian Carcinoma.	Norquist BM	JAMA oncology	2016	PMID: 26720728
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment.	Desmond A	JAMA oncology	2015	PMID: 26270727
Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers.	Domagala P	PloS one	2015	PMID: 26083025
Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis.	Cybulski C	The Lancet. Oncology	2015	PMID: 25959805
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.	Couch FJ	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 25452441
Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland.	Cybulski C	Clinical genetics	2015	PMID: 25330149
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
Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer.	Fernandes PH	Cancer	2014	PMID: 24415441
Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe.	Noskowicz M	Familial cancer	2014	PMID: 24061862
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
PALB2 mutations in familial breast and pancreatic cancer.	Hofstatter EW	Familial cancer	2011	PMID: 21365267
Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.	Casadei S	Cancer research	2011	PMID: 21285249
PALB2 mutations in German and Russian patients with bilateral breast cancer.	Bogdanova N	Breast cancer research and treatment	2011	PMID: 21165770
PALB2 analysis in BRCA2-like families.	Adank MA	Breast cancer research and treatment	2011	PMID: 20582465
Fanconi anemia gene mutations are not involved in sporadic Wilms tumor.	Adank MA	Pediatric blood & cancer	2010	PMID: 20589654
PALB2 mutations in European familial pancreatic cancer families.	Slater EP	Clinical genetics	2010	PMID: 20412113
A novel germline PALB2 deletion in Polish breast and ovarian cancer patients.	Dansonka-Mieszkowska A	BMC medical genetics	2010	PMID: 20122277
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 rs515726123 ...

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Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_024675.4(PALB2):c.509_510del (p.Arg170fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs515726123 ...