VCV000126623.89 - ClinVar

NM_024675.4(PALB2):c.172_175del (p.Gln60fs)

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.

(34)

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.172_175del (p.Gln60fs)

Variation ID: 126623 Accession: VCV000126623.89

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: 16p12.2 16: 23637886-23637889 (GRCh38) [ NCBI UCSC ] 16: 23649207-23649210 (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 4, 2013	Oct 20, 2024	Oct 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024675.4:c.172_175del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078951.2:p.Gln60fs	frameshift
NM_024675.4:c.172_175delTTGT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024675.3:c.172_175delTTGT
NC_000016.10:g.23637886ACAA[1]
NC_000016.9:g.23649207ACAA[1]
NG_007406.1:g.8465TTGT[1]
LRG_308:g.8465TTGT[1]

... more HGVS ... less HGVS

Protein change

Q60fs

Other names

Canonical SPDI

NC_000016.10:23637885:ACAAACAA:ACAA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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: CA151229 OMIM: 610355.0007 dbSNP: rs180177143 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.
DCTN5		-	-	GRCh38 GRCh37	9	45
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/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 20, 2024	RCV000114496.32
Pancreatic cancer, susceptibility to, 3	Pathogenic (3)	criteria provided, single submitter	Dec 14, 2023	RCV000114497.11
Hereditary cancer-predisposing syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 21, 2022	RCV000116073.22
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000212770.42
Breast and/or ovarian cancer	Pathogenic (1)	no assertion criteria provided	Jun 11, 2019	RCV001270993.4
Colorectal cancer	Likely pathogenic (1)	no assertion criteria provided	Jul 19, 2021	RCV001543616.4
Hereditary breast ovarian cancer syndrome	Pathogenic (2)	criteria provided, single submitter	Jan 2, 2019	RCV001193414.5
Fanconi anemia complementation group N	Pathogenic (1)	criteria provided, single submitter	Jun 13, 2019	RCV001781441.7
Familial cancer of breast Fanconi anemia complementation group N Pancreatic cancer, susceptibility to, 3	Pathogenic (1)	criteria provided, single submitter	Jan 11, 2022	RCV002490763.3
Breast-ovarian cancer, familial, susceptibility to, 5	Pathogenic (1)	criteria provided, single submitter	Oct 15, 2024	RCV004764849.1
PALB2-related disorder	Pathogenic (1)	no assertion criteria provided	May 24, 2024	RCV004739373.1
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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 (Apr 30, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002530642.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The PABL2 c.172_175del (p.Q60RfsX7) variant has been reported in individuals with breast cancer (PMID:21285249, 21618343, 24136930, 27488870, 30426508, 31312277). This variant has also been reported … (more) The PABL2 c.172_175del (p.Q60RfsX7) variant has been reported in individuals with breast cancer (PMID:21285249, 21618343, 24136930, 27488870, 30426508, 31312277). This variant has also been reported in individuals with ovarian cancer (PMID:22310028, 30322717,29052111). In a case-control study, this variant showed a strong association with an increased risk of breast cancer (OR=5.02; p=0.0016) (PMID:25959805). This variant causes a frameshift at amino acid 60 that results in premature termination 7 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in PALB2 are known to be pathogenic (PMID:25099575). This variant was observed in 1/10368 chromosomes in the Ashkenazi Jewish population and in 10/129184 chromosomes in the European(non-Finnish) population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org). The variant has been reported in ClinVar (Variation ID 126623). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (11) PubMed: 21285249‚ 21618343‚ 24136930‚ 27488870‚ 30426508‚ 31312277‚ 22310028‚ 30322717‚ 29052111‚ 25959805‚ 25099575
Pathogenic (Apr 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840029.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: A heterozygous c.172_17del (p.Gln60Argfs7) pathogenic variant in the PALB2 gene was detected in this individual. This variant has been previously described as disease-causing in pancreatic, … (more) A heterozygous c.172_17del (p.Gln60Argfs7) pathogenic variant in the PALB2 gene was detected in this individual. This variant has been previously described as disease-causing in pancreatic, breast and ovarian cancer (PMID: 19264984, 27038244, 25959805, 21285249, 21285249, 22310028, 22310028). Therefore, we consider this variant to be pathogenic. (less)
Pathogenic (Dec 09, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000704184.2 First in ClinVar: Dec 26, 2017 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PALB2 Sex: mixed
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: SCV000821755.2 First in ClinVar: Oct 10, 2018 Last updated: Mar 25, 2020	Comment: This variation is a deletion of 4 nucleotides from exon 3 of the PALB2 mRNA, causing a frameshift after codon 60 and the creation of … (more) This variation is a deletion of 4 nucleotides from exon 3 of the PALB2 mRNA, causing a frameshift after codon 60 and the creation of a premature translation stop signal 7 amino acid residues later p.(Gln60Argfs*7). This is expected to result in an absent or disrupted protein product. Truncating mutation in PALB2 gene are known to be pathogenic. The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126623). (less)
Pathogenic (Jan 02, 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: SCV001362215.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (5) PubMed: 21618343‚ 21285249‚ 27616075‚ 25959805‚ 19264984 Comment: Variant summary: PALB2 c.172_175delTTGT (p.Gln60ArgfsX7) 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.172_175delTTGT (p.Gln60ArgfsX7) 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. The variant allele was found at a frequency of 4e-05 in 277228 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00016), allowing no conclusion about variant significance. c.172_175delTTGT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Hellebrand 2011, Casadei 2011 ,Kraus 2016) and pancreatic cancer (Jones 2009). These data indicate that the variant is very likely to be associated with disease. In addition, a case-control study found this variant to be present at a significantly higher frequency in breast cancer patients than in unaffected controls (OR=5.02; p=0.0016) (Cybulski 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (9)/likely pathogenic(1). Based on the evidence outlined above, the variant was 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: SCV001446510.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Breast carcinoma (present) , Endometrial carcinoma (present) Sex: female
Pathogenic (Apr 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449955.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 6
Pathogenic (Sep 17, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149982.13 First in ClinVar: May 14, 2014 Last updated: Apr 17, 2019	Comment: Recurrent variant in Polish and Czech populations (Janatova 2013, Cybulski 2015); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a … (more) Recurrent variant in Polish and Czech populations (Janatova 2013, Cybulski 2015); 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; Case control studies suggest this variant is associated with breast and pancreatic cancer (Cybulski 2015, Lener 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jones 2009, Casadei 2011, Hellebrand 2011, Janatova 2013, Thompson 2015, Kluska 2017, Kraus 2017); This variant is associated with the following publications: (PMID: 26283626, 22310028, 24136930, 30716324, 19264984, 21285249, 25330149, 25959805, 21618343, 27038244, 23935381, 24982446, 28008555, 27488870, 26843898, 27099641, 27616075, 23242139, 26681312, 27757719, 28279176, 28281021, 28454591, 28724667, 28657667, 25452441, 24549055, 29052111, 29753700, 30086788, 30426508, 30322717, 31159747, 30113427, 31312277, 31757951, 29625052, 26689913, 32052252, 31447099, 31948886, 32339256) (less)
Pathogenic (Jun 03, 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: SCV002580281.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP	Number of individuals with the variant: 1 Sex: female
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: SCV002762828.2 First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023	Comment: PVS1, 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: SCV002010978.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Aug 09, 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: SCV000601740.4 First in ClinVar: Mar 08, 2017 Last updated: Jan 06, 2024	Publications: PubMed (15) PubMed: 32052252‚ 31948886‚ 32339256‚ 31757951‚ 31159747‚ 29052111‚ 29753700‚ 21285249‚ 19264984‚ 24549055‚ 24136930‚ 25330149‚ 25452441‚ 22310028‚ 21618343 Comment: This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or … (more) This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer, pancreatic cancer, prostate cancer, and medulloblastoma (PMID: 32339256 (2020), 31948886 (2020), 29753700 (2018), 29052111 (2018), 25452441 (2015), 24549055 (2014), and 19264984 (2009)). In addition, it has been reported in an individual with Fanconi Anemia, compound heterozygous with a PALB2 splice variant (PMID: 32052252 (2020)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jun 13, 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: SCV002016517.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pancreatic cancer, susceptibility to, 3 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004242403.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: Criteria applied: PVS1,PS4 Clinical Features: Neoplasm of the pancreas (present) Sex: male
Pathogenic (Mar 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002505617.3 First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024	Comment: Criteria applied: PVS1,PS4,PM5_SUP Clinical Features: Family history of cancer (present) Sex: female
Pathogenic (Sep 22, 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: SCV000172718.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 19264984‚ 21285249‚ 22310028‚ 24136930‚ 25959805‚ 28279176‚ 29052111‚ 29753700 Comment: The c.172_175delTTGT (p.Q60Rfs7) alteration, located in exon 3 (coding exon 3) of the PALB2 gene, consists of a deletion of 4 nucleotides from position 172 … (more) The c.172_175delTTGT (p.Q60Rfs7) alteration, located in exon 3 (coding exon 3) of the PALB2 gene, consists of a deletion of 4 nucleotides from position 172 to 175, causing a translational frameshift with a predicted alternate stop codon after 7 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in pancreatic, breast, and ovarian cancer patients, including multiple individuals with family histories significant for PALB2-related cancers (Jones, 2009; Casadei, 2011; Prokofyeva, 2012; Janatova, 2013; Cybulski, 2015; Kluska, 2017; Myszka, 2018). It was also seen in a patient with medulloblastoma (Waszak, 2018). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202018.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 5 Affected status: yes Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV005374613.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024	Comment: ACMG/ClinGen VCEP PALB2: PVS1, PS4, PM5_Supporting Clinical Features: Breast carcinoma (present)
Pathogenic (Feb 01, 2024)	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: SCV001247812.23 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PALB2: PVS1, PS4, PS3:Supporting Number of individuals with the variant: 3
Likely pathogenic (Jun 01, 2015)	criteria provided, single submitter (Thompson et al. (Breast Cancer Res. 2015)) Method: case-control	Familial cancer of breast Cases recruited through familial (more...) Affected status: yes Allele origin: germline	Cancer Genetics Laboratory, Peter MacCallum Cancer Centre Accession: SCV000267958.1 First in ClinVar: May 11, 2016 Last updated: May 11, 2016	Publications: PubMed (1) PubMed: 26283626 Number of individuals with the variant: 1 Sex: female Geographic origin: Australia
Pathogenic (Aug 15, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785469.2 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018	Publications: PubMed (1) PubMed: 24136930
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: SCV001499699.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Jan 11, 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: SCV002811651.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 03, 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: SCV004019725.1 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, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000685897.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (15) PubMed: 19264984‚ 21285249‚ 21618343‚ 22310028‚ 24136930‚ 25099575‚ 25452441‚ 25959805‚ 26283626‚ 27038244‚ 27616075‚ 28724667‚ 29052111‚ 29753700‚ 33471991 Comment: This variant deletes 4 nucleotides in exon 3 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 4 nucleotides in exon 3 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 over 15 individuals affected with breast and/or ovarian cancer (PMID: 21285249, 21618343, 22310028, 24136930, 25099575, 25452441, 26283626, 27616075, 28724667, 29052111), 2 individuals affected with pancreatic cancer (PMID: 19264984, 27038244) and an individual affected with medulloblastoma (PMID: 29753700). This variant also has been reported in a breast cancer case-control study in 40/12529 cases and 10/4702 unaffected individuals (OR = 4.02, 95% CI 1.6 to 16.2) and a breast cancer case-control meta-analysis in 24/60466 cases and 9/53461 unaffected individuals (OR = 2.358, 95%CI 1.096 to 5.074) (PMID: 25959805, 33471991; Leiden Open Variation Database DB-ID PALB2_010002). This variant has been identified in 12/282872 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: SCV000290814.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024	Publications: PubMed (13) PubMed: 28492532‚ 17200668‚ 17200671‚ 17200672‚ 24136930‚ 25099575‚ 19264984‚ 21285249‚ 21618343‚ 22310028‚ 25959805‚ 27038244‚ 27616075 Comment: This sequence change creates a premature translational stop signal (p.Gln60Argfs7) 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.Gln60Argfs7) 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 (rs180177143, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 19264984, 21285249, 21618343, 22310028, 24136930, 25959805, 27038244, 27616075). ClinVar contains an entry for this variant (Variation ID: 126623). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 28, 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: SCV005199037.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
risk factor (Apr 10, 2009)	no assertion criteria provided Method: literature only	PANCREATIC CANCER, SUSCEPTIBILITY TO, 3 Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000021461.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 19264984 Comment on evidence: In a patient with pancreatic cancer (PNCA3; 613348) whose tumor DNA had previously been sequenced, Jones et al. (2009) found a heterozygous germline deletion of … (more) In a patient with pancreatic cancer (PNCA3; 613348) whose tumor DNA had previously been sequenced, Jones et al. (2009) found a heterozygous germline deletion of 4 basepairs in the PALB2 gene, TTGT approximately at nucleotide 172 in exon 3, that produced a frameshift at codon 58. The pancreatic cancer had also somatically acquired a transition mutation, a C-to-T transition at a canonical splice site for exon 10 (IVS10+2). (less)
Likely pathogenic (Jul 19, 2021)	no assertion criteria provided Method: research	Colorectal cancer (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine. Accession: SCV001754809.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Comment: The Leu58fs variant in PALB2 has been reported in 1 Chinese family with autosomal dominant predisposition in familial colorectal cancer (CRC). Age: 50-59 years Sex: male Ethnicity/Population group: Chinese Geographic origin: China
Pathogenic (Oct 18, 2021)	no assertion criteria provided Method: clinical testing	Pancreatic cancer, susceptibility to, 3 Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002029194.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
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: SCV002588982.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (May 24, 2024)	no assertion criteria provided Method: clinical testing	PALB2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005364629.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PALB2 c.172_175delTTGT variant is predicted to result in a frameshift and premature protein termination (p.Gln60Argfs7). This variant has been frequently reported as pathogenic in … (more) The PALB2 c.172_175delTTGT variant is predicted to result in a frameshift and premature protein termination (p.Gln60Argfs7). This variant has been frequently reported as pathogenic in individuals with a history of breast, pancreatic, and ovarian cancers (Jones et al. 2009. PubMed ID: 19264984; Lener et al. 2016. PubMed ID: 27038244; Casadei et al. 2011. PubMed ID: 21285249; Hellebrand et al. 2011. PubMed ID: 21618343; Kraus et al. 2017. PubMed ID: 27616075; Prokofyeva et al. 2012. PubMed ID: 22310028). Of note, this variant is also reported to be a founder variant in individuals of Czech and Polish ancestry (Lener et al. 2016. PubMed ID: 27038244). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as Pathogenic/Likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126623/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Feb 28, 2020)	no assertion criteria provided Method: curation	not provided Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001192937.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (9) PubMed: 19264984‚ 21285249‚ 21618343‚ 22310028‚ 24136930‚ 24549055‚ 25099575‚ 25330149‚ 25452441 Comment: Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, 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: SCV001451805.1 First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020	Publications: PubMed (1) PubMed: 32295079 Number of individuals with the variant: 3 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
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Comment:

A heterozygous c.172_17del (p.Gln60Argfs*7) pathogenic variant in the PALB2 gene was detected in this individual. This variant has been previously described as disease-causing in pancreatic, breast and ovarian cancer (PMID: 19264984, 27038244, 25959805, 21285249, 21285249, 22310028, 22310028). Therefore, we consider this variant to be pathogenic.

Comment:

This variation is a deletion of 4 nucleotides from exon 3 of the PALB2 mRNA, causing a frameshift after codon 60 and the creation of a premature translation stop signal 7 amino acid residues later p.(Gln60Argfs*7). This is expected to result in an absent or disrupted protein product. Truncating mutation in PALB2 gene are known to be pathogenic. The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126623).

Comment:

Variant summary: PALB2 c.172_175delTTGT (p.Gln60ArgfsX7) 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. The variant allele was found at a frequency of 4e-05 in 277228 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00016), allowing no conclusion about variant significance. c.172_175delTTGT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Hellebrand 2011, Casadei 2011 ,Kraus 2016) and pancreatic cancer (Jones 2009). These data indicate that the variant is very likely to be associated with disease. In addition, a case-control study found this variant to be present at a significantly higher frequency in breast cancer patients than in unaffected controls (OR=5.02; p=0.0016) (Cybulski 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (9)/likely pathogenic(1). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Recurrent variant in Polish and Czech populations (Janatova 2013, Cybulski 2015); 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; Case control studies suggest this variant is associated with breast and pancreatic cancer (Cybulski 2015, Lener 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jones 2009, Casadei 2011, Hellebrand 2011, Janatova 2013, Thompson 2015, Kluska 2017, Kraus 2017); This variant is associated with the following publications: (PMID: 26283626, 22310028, 24136930, 30716324, 19264984, 21285249, 25330149, 25959805, 21618343, 27038244, 23935381, 24982446, 28008555, 27488870, 26843898, 27099641, 27616075, 23242139, 26681312, 27757719, 28279176, 28281021, 28454591, 28724667, 28657667, 25452441, 24549055, 29052111, 29753700, 30086788, 30426508, 30322717, 31159747, 30113427, 31312277, 31757951, 29625052, 26689913, 32052252, 31447099, 31948886, 32339256)

Comment:

This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer, pancreatic cancer, prostate cancer, and medulloblastoma (PMID: 32339256 (2020), 31948886 (2020), 29753700 (2018), 29052111 (2018), 25452441 (2015), 24549055 (2014), and 19264984 (2009)). In addition, it has been reported in an individual with Fanconi Anemia, compound heterozygous with a PALB2 splice variant (PMID: 32052252 (2020)). Based on the available information, this variant is classified as pathogenic.

Comment:

The c.172_175delTTGT (p.Q60Rfs*7) alteration, located in exon 3 (coding exon 3) of the PALB2 gene, consists of a deletion of 4 nucleotides from position 172 to 175, causing a translational frameshift with a predicted alternate stop codon after 7 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in pancreatic, breast, and ovarian cancer patients, including multiple individuals with family histories significant for PALB2-related cancers (Jones, 2009; Casadei, 2011; Prokofyeva, 2012; Janatova, 2013; Cybulski, 2015; Kluska, 2017; Myszka, 2018). It was also seen in a patient with medulloblastoma (Waszak, 2018). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This variant deletes 4 nucleotides in exon 3 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 over 15 individuals affected with breast and/or ovarian cancer (PMID: 21285249, 21618343, 22310028, 24136930, 25099575, 25452441, 26283626, 27616075, 28724667, 29052111), 2 individuals affected with pancreatic cancer (PMID: 19264984, 27038244) and an individual affected with medulloblastoma (PMID: 29753700). This variant also has been reported in a breast cancer case-control study in 40/12529 cases and 10/4702 unaffected individuals (OR = 4.02, 95% CI 1.6 to 16.2) and a breast cancer case-control meta-analysis in 24/60466 cases and 9/53461 unaffected individuals (OR = 2.358, 95%CI 1.096 to 5.074) (PMID: 25959805, 33471991; Leiden Open Variation Database DB-ID PALB2_010002). This variant has been identified in 12/282872 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.Gln60Argfs*7) 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 (rs180177143, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 19264984, 21285249, 21618343, 22310028, 24136930, 25959805, 27038244, 27616075). ClinVar contains an entry for this variant (Variation ID: 126623). For these reasons, this variant has been classified as Pathogenic.

Comment:

The PALB2 c.172_175delTTGT variant is predicted to result in a frameshift and premature protein termination (p.Gln60Argfs*7). This variant has been frequently reported as pathogenic in individuals with a history of breast, pancreatic, and ovarian cancers (Jones et al. 2009. PubMed ID: 19264984; Lener et al. 2016. PubMed ID: 27038244; Casadei et al. 2011. PubMed ID: 21285249; Hellebrand et al. 2011. PubMed ID: 21618343; Kraus et al. 2017. PubMed ID: 27616075; Prokofyeva et al. 2012. PubMed ID: 22310028). Of note, this variant is also reported to be a founder variant in individuals of Czech and Polish ancestry (Lener et al. 2016. PubMed ID: 27038244). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as Pathogenic/Likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126623/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)	Method not provided	Result not provided	Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine. Accession: SCV001754809.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
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
Novel intronic variant in PALB2 gene and effective prevention of Fanconi anemia in family.	Viakhireva I	Familial cancer	2020	PMID: 32052252
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer.	Wu Y	European urology oncology	2020	PMID: 31948886
Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2.	Boonen RACM	Nature communications	2019	PMID: 31757951
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
The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants.	Schubert S	International journal of cancer	2019	PMID: 30426508
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.	Waszak SM	The Lancet. Oncology	2018	PMID: 29753700
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
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland.	Kluska A	BMC medical genomics	2017	PMID: 28279176
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2.	Kraus C	International journal of cancer	2017	PMID: 27616075
The Prevalence of Founder Mutations among Individuals from Families with Familial Pancreatic Cancer Syndrome.	Lener MR	Cancer research and treatment	2017	PMID: 27488870
Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?	Lener MR	International journal of cancer	2016	PMID: 27038244
Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.	Thompson ER	Breast cancer research : BCR	2015	PMID: 26283626
Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis.	Cybulski C	The Lancet. Oncology	2015	PMID: 25959805
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
Breast-cancer risk in families with mutations in PALB2.	Antoniou AC	The New England journal of medicine	2014	PMID: 25099575
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes.	Castéra L	European journal of human genetics : EJHG	2014	PMID: 24549055
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
Rare occurrence of PALB2 mutations in ovarian cancer patients from the Volga-Ural region.	Prokofyeva D	Clinical genetics	2012	PMID: 22310028
Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer.	Hellebrand H	Human mutation	2011	PMID: 21618343
Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer.	Casadei S	Cancer research	2011	PMID: 21285249
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.	Jones S	Science (New York, N.Y.)	2009	PMID: 19264984
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PALB2	-	-	-	-
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Text-mined citations for rs180177143 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_024675.4(PALB2):c.172_175del (p.Gln60fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs180177143 ...