ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3116del (p.Asn1039fs)

dbSNP: rs180177133
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 23
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131150 SCV000186091 pathogenic Hereditary cancer-predisposing syndrome 2024-10-30 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; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Woodward ER et al. Genet Med, 2021 Oct;23:1969-1976; Kondrashova O et al. Cancers (Basel), 2021 04;13; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000114595 SCV000260801 pathogenic Familial cancer of breast 2024-01-28 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. 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.
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 2022-02-09 criteria provided, single submitter clinical testing 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)
Counsyl RCV000114595 SCV000488804 pathogenic Familial cancer of breast 2016-06-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131150 SCV000690900 pathogenic Hereditary cancer-predisposing syndrome 2022-12-13 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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least 12 individuals affected with breast cancer (PMID: 17200668, 25452441, 26283626, 33471991, 34113003; Leiden Open Variation Database DB-ID PALB2_000014), and two individuals affected with pancreatic, prostate and stomach cancer (PMID: 19264984, 26845104), and in at least 4 unaffected individuals (PMID: 26283626, 33471991; Leiden Open Variation Database DB-ID PALB2_000014). This variant also has been reported in a compound heterozygous carrier with a second PALB2 truncation variation 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 2024-11-08 criteria provided, single submitter clinical testing The PALB2 c.3116del (p.Asn1039Ilefs*2) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 17200668 (2007), 25099575 (2014), 25452441 (2015), 26283626 (2015), 34326862 (2021)), pancreatic cancer (PMID: 19264984 (2009), 20412113 (2010), 29922827 (2018)), endometrial cancer (PMID: 36744932 (2023)), and ovarian cancer (PMID: 36169650 (2022)). This variant was also identified in an individual with Fanconi anemia (PMID: 17200671 (2007)). A published functional study has shown that this variant results in no protein expression in Fanconi anemia patient cells with other biallelic truncating variants (PMID: 17200671 (2007)). The frequency of this variant in the general population, 0.000027 (3/112938 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Sema4, Sema4 RCV000131150 SCV002530755 pathogenic Hereditary cancer-predisposing syndrome 2022-01-30 criteria provided, single submitter curation
Genetics and Molecular Pathology, SA Pathology RCV000114595 SCV002556654 pathogenic Familial cancer of breast 2020-04-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002498485 SCV002811104 pathogenic Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3 2021-08-17 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149787 SCV003838770 pathogenic Breast and/or ovarian cancer 2021-11-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235042 SCV003934023 pathogenic Hereditary breast ovarian cancer syndrome 2023-05-11 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3116delA (p.Asn1039IlefsX2) 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 1.2e-05 in 249950 control chromosomes. c.3116delA has been reported in the literature as a biallelic genotype in at least one individual affected with Fanconi Anemia and childhood cancer and in the heterozygous state in multiple individuals affected with breast cancer (e.g. Reid_2007, Antoniou_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25099575, 17200671). Fifteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=14)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc. RCV000114595 SCV004019610 pathogenic Familial cancer of breast 2023-03-31 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV000114595 SCV004202144 pathogenic Familial cancer of breast 2024-02-05 criteria provided, single submitter clinical testing
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, susceptibility to, 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.
PreventionGenetics, part of Exact Sciences RCV004739376 SCV005360165 pathogenic PALB2-related disorder 2024-07-17 no assertion criteria provided clinical testing The PALB2 c.3116delA variant is predicted to result in a frameshift and premature protein termination (p.Asn1039Ilefs*2). This variant has been reported in individuals with breast, pancreatic, and prostate cancer (Rahman et al. 2007. PubMed ID: 17200668; Jones et al. 2009. PubMed ID: 19264984; Slater et al. 2010. PubMed ID: 20412113; Matejcic et al. 2020. PubMed ID: 32832836). It was also reported in the compound heterozygous state in an individual with a history of acute myeloid leukemia, neuroblastoma, and Fanconi Anemia Reid et al. 2007. PubMed ID: 17200671). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as Pathogenic/Likely Pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126715/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.