ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic/Likely pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 16
- First in ClinVar:
- Apr 4, 2013
- Most recent Submission:
- Jun 30, 2022
- Last evaluated:
- Feb 9, 2022
- Accession:
- VCV000126715.23
- Variation ID:
- 126715
- Description:
- 1bp deletion
Help
NM_024675.4(PALB2):c.3116del (p.Asn1039fs)
- Allele ID
- 132225
- Variant type
- Deletion
- Variant length
- 1 bp
- Cytogenetic location
- 16p12.2
- Genomic location
- 16: 23614089 (GRCh38) GRCh38 UCSC
- 16: 23625410 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024675.4:c.3116del MANE Select NP_078951.2:p.Asn1039fs frameshift NM_024675.3:c.3116delA NC_000016.10:g.23614090del NC_000016.9:g.23625411del NG_007406.1:g.32269del LRG_308:g.32269del - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000016.10:23614088:TT:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA151245
- OMIM: 610355.0005
- OMIM: 610355.0009
- dbSNP: rs180177133
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic/Likely pathogenic | 4 | criteria provided, multiple submitters, no conflicts | Dec 8, 2021 | RCV000114595.14 | |
| Pathogenic | 5 | criteria provided, multiple submitters, no conflicts | Jan 30, 2022 | RCV000131150.11 | |
| Pathogenic | 3 | criteria provided, multiple submitters, no conflicts | Feb 9, 2022 | RCV000235691.9 | |
| risk factor | 1 | no assertion criteria provided | Feb 1, 2007 | RCV000001309.3 | |
| Pathogenic | 1 | no assertion criteria provided | Feb 1, 2007 | RCV000114596.4 | |
| risk factor | 1 | no assertion criteria provided | Apr 10, 2009 | RCV000114597.6 | |
| Pathogenic | 1 | no assertion criteria provided | - | RCV001357097.2 |
Clinical features observed in individuals with this variant
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
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Pathogenic
(Nov 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine,University of Washington
Accession: SCV000266106.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
Clinical Features:
stomach cancer (present)
Age: 30-39 years
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Likely pathogenic
(Jun 01, 2015)
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criteria provided, single submitter
Method: case-control
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Familial cancer of breast
Cases recruited through familial
(more...)
Affected status: yes, no
Allele origin:
germline
|
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre
Accession: SCV000267972.1
First in ClinVar: May 11, 2016 Last updated: May 11, 2016 |
Observation 1:
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Sex: female
Geographic origin: Australia
Observation 2:
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
Sex: female
Geographic origin: Australia
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Pathogenic
(Jun 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488804.1
First in ClinVar: May 11, 2016 Last updated: May 11, 2016 |
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Pathogenic
(Jan 26, 2018)
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criteria provided, single submitter
Method: research
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
Academic Department of Medical Genetics, University of Cambridge
Accession: SCV000992219.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019
Comment:
Identified as part of research study of individuals with multiple primary tumours referred for genetic assessment
|
Comment:
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Clinical Features:
Breast carcinoma (present) , Angiosarcoma (present) , Neoplasia of the nasopharynx (present)
Zygosity: 1 Single Heterozygote
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: no
Allele origin:
germline
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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001434292.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This variant leads to a translational frameshift and the introduction of a premature termination codon at position 2 of the new reading frame. The variant … (more)
This variant leads to a translational frameshift and the introduction of a premature termination codon at position 2 of the new reading frame. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PALB2 is a well-established mechanism of disease for increased breast cancer risk (Rahman 2007, Janatova 2013, Antoniou 2014). This variant has an allele frequency of 0.00001 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with Fanconi anemia, as well as individuals with breast cancer and pancreatic cancer (Reid 2007, Rahman 2007, Jones 2009, Slater 2010, Couch 2015, Shirts 2016). Thus, this variant is interpreted as pathogenic. PM2; PVS1 (less)
Indication for testing: Family history of breast cancer
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Pathogenic
(Oct 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186091.7
First in ClinVar: Aug 06, 2014 Last updated: Jun 22, 2020 |
Comment:
The c.3116delA pathogenic mutation, located in coding exon 11 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3116, causing … (more)
The c.3116delA pathogenic mutation, located in coding exon 11 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3116, causing a translational frameshift with a predicted alternate stop codon (p.N1039Ifs*2). This mutation has been reported in individuals affected with familial breast cancer and familial pancreatic cancer (Rahman N et al. Nat. Genet. 2007 Feb;39(2):165-7; Jones S et al. Science 2009 Apr 10;324(5924):217; Slater EP et al. Clin. Genet. 2010 Nov;78(5): 490-4; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). It has also been identified in conjunction with another PALB2 mutation in an individual affected with Fanconi anemia type N (Reid S et al. Nat. Genet. 2007 Feb;39(2):162-4). 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)
Number of individuals with the variant: 1
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Pathogenic
(Feb 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Health, Inc
Accession: SCV000690900.3
First in ClinVar: Feb 19, 2018 Last updated: Jun 19, 2021 |
Comment:
This variant changes 1 nucleotide in exon 11 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 11 of the PALB2 gene, creating a 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 at least 5 individuals affected with breast cancer (PMID: 17200668, 25452441, 26283626) and 5 suspected hereditary breast cancer families (PMID: 25099575) and an individual affected with pancreatic and prostate cancer (PMID: 19264984). This variant also has been reported in an individual affected with stomach cancer (PMID: 26845104) and an unaffected individual in a breast cancer case-control study (PMID: 26283626). This variant also has been observed in an individual with a pathogenic PALB2 covariant who is affected with Fanconi anemia (PMID: 17200671). This variant has been identified in 3/249950 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)
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Pathogenic
(Aug 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470039.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 11, 2022 |
Comment:
This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, it has been reported in individuals affected with breast cancer … (more)
This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, it has been reported in individuals affected with breast cancer (PMID: 17200668 (2007), 25099575 (2014), 25452441 (2015), 26283626 (2015)), pancreatic cancer (PMID: 19264984 (2009), 20412113 (2010)), Fanconi anemia (PMID: 17200671 (2007)), and other cancers (PMID: 29909963 (2018)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000260801.9
First in ClinVar: Jan 31, 2016 Last updated: Jun 18, 2022 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn1039Ilefs*2) 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.Asn1039Ilefs*2) 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 (rs180177133, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia, breast cancer, pancreatic cancer, and stomach cancer (PMID: 17200668, 17200671, 19264984, 20412113, 25452441, 26845104). ClinVar contains an entry for this variant (Variation ID: 126715). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 30, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4,Sema4
Accession: SCV002530755.1
First in ClinVar: Jun 30, 2022 Last updated: Jun 30, 2022
Comment:
The PALB2 c.3116delA (p.N1039IfsX2) variant has been reported in heterozygosity in multiple individuals with pancreatic and breast cancer (PMID: 20412113, 17200668, among others). It has … (more)
The PALB2 c.3116delA (p.N1039IfsX2) variant has been reported in heterozygosity in multiple individuals with pancreatic and breast cancer (PMID: 20412113, 17200668, among others). It has been reported in a large case-control study of breast cancer in 12/60466 cases and 4/53461 controls (PMID: 33471991) and in case-control study with breast cancer in 1/1996 cases and in 1/1998 controls (PMID: 26283626). This variant causes a frameshift at amino acid 1039 that results in premature termination 2 amino acids downstream. At this location, this variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function of the PALB2 gene is an established disease mechanism (PMID: 17200668). This variant was observed in 3/112938 chromosomes in the Non-Finnish European population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 126715). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000293156.11
First in ClinVar: Jul 24, 2016 Last updated: Jun 18, 2022 |
Comment:
Observed in individuals with PALB2-related cancers (Rahman 2007, Jones 2009, Slater 2010, Antoniou 2014, Thompson 2015); Frameshift variant predicted to result in protein truncation or … (more)
Observed in individuals with PALB2-related cancers (Rahman 2007, Jones 2009, Slater 2010, Antoniou 2014, Thompson 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18302019, 20858716, 17200668, 19264984, 20412113, 25099575, 25452441, 26283626, 23935381, 21618343, 21165770, 19763819, 21932393, 23935836, 27595995, 26845104, 28454591, 26786923, 28779002, 29909963, 34113003, 32853339, 32885271, 32581362, 32832836, 31447099, 17200671) (less)
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risk factor
(Feb 01, 2007)
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no assertion criteria provided
Method: literature only
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BREAST CANCER, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021459.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a North American family with Fanconi anemia, complementation group N (FANCN; 610832), Reid et al. (2007) found a 1-bp deletion, 3116delA (N1039fs), in exon … (more)
In a North American family with Fanconi anemia, complementation group N (FANCN; 610832), Reid et al. (2007) found a 1-bp deletion, 3116delA (N1039fs), in exon 11 of the PALB2 gene in compound heterozygosity with a premature termination mutation (610355.0003). In 3 individuals with breast cancer (114480) from separate unrelated families with familial breast cancer, Rahman et al. (2007) found a frameshift mutation in the PALB2 gene: 3116delA, asn1039fs. (less)
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Pathogenic
(Feb 01, 2007)
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no assertion criteria provided
Method: literature only
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FANCONI ANEMIA, COMPLEMENTATION GROUP N
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021458.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a North American family with Fanconi anemia, complementation group N (FANCN; 610832), Reid et al. (2007) found a 1-bp deletion, 3116delA (N1039fs), in exon … (more)
In a North American family with Fanconi anemia, complementation group N (FANCN; 610832), Reid et al. (2007) found a 1-bp deletion, 3116delA (N1039fs), in exon 11 of the PALB2 gene in compound heterozygosity with a premature termination mutation (610355.0003). In 3 individuals with breast cancer (114480) from separate unrelated families with familial breast cancer, Rahman et al. (2007) found a frameshift mutation in the PALB2 gene: 3116delA, asn1039fs. (less)
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risk factor
(Apr 10, 2009)
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no assertion criteria provided
Method: literature only
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PANCREATIC CANCER, SUSCEPTIBILITY TO, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021463.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 22, 2019 |
Comment on evidence:
In a patient with familial pancreatic cancer (PNCA3; 613348), Jones et al. (2009) identified a heterozygous germline deletion of adenine at nucleotide 3116 in exon … (more)
In a patient with familial pancreatic cancer (PNCA3; 613348), Jones et al. (2009) identified a heterozygous germline deletion of adenine at nucleotide 3116 in exon 11 of the PALB2 gene. (less)
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Pathogenic
(May 13, 2019)
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no assertion criteria provided
Method: curation
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not provided
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001193357.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment:
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz.
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine,Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552448.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PALB2 p.Asn1039IlefsX2 variant was identified in 16 of 15604 proband chromosomes (frequency: 0.001) from individuals or families affected with Fanconi anemia, breast cancer, pancreatic … (more)
The PALB2 p.Asn1039IlefsX2 variant was identified in 16 of 15604 proband chromosomes (frequency: 0.001) from individuals or families affected with Fanconi anemia, breast cancer, pancreatic cancer, and stomach cancer and was present in 1 of 3996 control chromosomes (frequency: 0.00025) from healthy individuals (Thompson_2015, Slater_2010, Reid_2007, Rahman_2007, Jones_2009, Zheng_2012, Southey_2013, Couch_2015, Shirts_2016, Antoniou_2014). The variant was also identified in the following databases: dbSNP (ID: rs180177133) as “With Pathogenic allele”, ClinVar and Clinvitae (13x as pathogenic by Ambry Genetics, Invitae, GeneDx, Color Geneomics, Counsyl, PALB2 database, OMIM and as likely pathogenic by Peter MacCallum Cancer Center) and Zhejiang Colon Cancer Database. The variant was not identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 3 of 244820 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). It was observed in the European (Non-Finnish) population in 3 of 110928 chromosomes (freq: 0.000027), but not in other populations. Protein blot analysis of lymphoblastoid cells from individuals with biallelic PALB2 mutations has demonstrated that the mutation results in a null allele confirming its pathogenicity; this study has shown that biallelic pathogenic mutations in PALB2 in affected families cause a new subtype of Fanconi anemia and cancer in early childhood (Reid_2007). The c.3116delA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1039 and leads to a premature stop codon 2 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 related cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Functional evidence
Help| 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. |
Citations for this variant
Help| 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 |
| Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. | Whitworth J | American journal of human genetics | 2018 | PMID: 29909963 |
| Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
| Improving performance of multigene panels for genomic analysis of cancer predisposition. | Shirts BH | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845104 |
| Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. | Thompson ER | Breast cancer research : BCR | 2015 | PMID: 26283626 |
| 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 |
| Breast-cancer risk in families with mutations in PALB2. | Antoniou AC | The New England journal of medicine | 2014 | PMID: 25099575 |
| The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. | Janatova M | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2013 | PMID: 24136930 |
| PALB2 mutations in European familial pancreatic cancer families. | Slater EP | Clinical genetics | 2010 | PMID: 20412113 |
| Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. | Jones S | Science (New York, N.Y.) | 2009 | PMID: 19264984 |
| Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. | García MJ | Breast cancer research and treatment | 2009 | PMID: 18302019 |
| 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 |
Text-mined citations for rs180177133...
HelpThese 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 Jun 30, 2022