ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3116del (p.Asn1039fs) (rs180177133)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131150 SCV000186091 pathogenic Hereditary cancer-predisposing syndrome 2018-10-09 criteria provided, single submitter clinical testing 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.
Invitae RCV000114595 SCV000260801 pathogenic Familial cancer of breast 2020-10-23 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Fanconi anemia, breast cancer, pancreatic cancer, and stomach cancer (PMID: 17200671, 17200668, 19264984, 20412113, 25452441, 26845104). ClinVar contains an entry for this variant (Variation ID: 126715). Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000131150 SCV000266106 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114595 SCV000267972 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
GeneDx RCV000235691 SCV000293156 pathogenic not provided 2017-12-29 criteria provided, single submitter clinical testing This deletion of one nucleotide in PALB2 is denoted c.3116delA at the cDNA level and p.Asn1039IlefsX2 (N1039IfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is agGA[delA]TTTA, where the capital letters are exonic and lowercase letters are intronic. The deletion causes a frameshift, which changes an Asparagine to an Isoleucine at codon 1039, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PALB2 c.3116delA has been observed, in the compound heterozygous state, in an individual with Fanconi Anemia and a history of neuroblastoma and acute myeloid leukemia (Reid 2007). Additionally, this variant has been seen in association with familial breast and pancreatic cancer (Rahman 2007, Jones 2009, Slater 2010, Antoniou 2014, Thompson 2015). We consider this variant to be pathogenic.
Counsyl RCV000114595 SCV000488804 pathogenic Familial cancer of breast 2016-06-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131150 SCV000690900 pathogenic Hereditary cancer-predisposing syndrome 2021-02-11 criteria provided, single submitter clinical testing 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.
Academic Department of Medical Genetics, University of Cambridge RCV000131150 SCV000992219 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research 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.
Division of Medical Genetics, University of Washington RCV000114595 SCV001434292 pathogenic Familial cancer of breast 2020-01-22 criteria provided, single submitter clinical testing 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235691 SCV001470039 pathogenic not provided 2020-08-27 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
OMIM RCV000114596 SCV000021458 pathogenic Fanconi anemia, complementation group N 2007-02-01 no assertion criteria provided literature only
OMIM RCV000001309 SCV000021459 risk factor Breast cancer, susceptibility to 2007-02-01 no assertion criteria provided literature only
OMIM RCV000114597 SCV000021463 risk factor Pancreatic cancer 3 2009-04-10 no assertion criteria provided literature only
Leiden Open Variation Database RCV000235691 SCV001193357 pathogenic not provided 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357097 SCV001552448 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing 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.

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