ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3113G>A (p.Trp1038Ter) (rs180177132)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212822 SCV000150005 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted PALB2 c.3113G>A at the cDNA level and p.Trp1038Ter (W1038X) at the protein level. This is a nonsense variant, changing a Tryptophan to a premature stop codon. In an mRNA-based assay, Casadei et al. (2011) showed that the expected transcript, an immediate stop codon, was not the only aberrant transcript produced by this variant. Two other alternate transcripts, an in-frame deletion of exon 10 and an out-of-frame deletion of 31 base pairs in exon 10, were also identified and are a result of the proximity of the variant to the splice donor site. Additionally, Teo et al. (2013) confirmed the presence of these two alternate transcripts but failed to identify the expected nonsense transcript in an mRNA-based assay. The in-frame deletion of exon 10 is located within a region of interaction with BRCA2 which is thought to be important to PALB2 protein function, and both the expected transcript and the deletion of 31 base pairs are predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (Casadei 2011, Teo 2013). This variant has been reported in several individuals with a personal and/or family history of breast cancer (Rahman 2007, Southey 2010, Wong 2011, Teo 2013, Southey 2016, Winship 2016) and is considered a pathogenic founder variant in the British population (Hartley 2014). PALB2 Trp1038Ter has been associated with a significantly increased risk for breast cancer in a large, multi-center case-control analysis (Southey 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000114591 SCV000166660 pathogenic Familial cancer of breast 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1038 (p.Trp1038*) of the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in individuals and families affected with breast cancer, with evidence of co-segregation with disease (PMID: 17200668, 21182766, 21285249, 23471749). ClinVar contains an entry for this variant (Variation ID: 126711). This variant also falls in the last nucleotide of the exon, which is part of the consensus splice site. Experimental studies have shown that this variant causes altered splicing, creating different PALB2 transcripts in lymphoblastoid cells derived from individuals with breast cancer (PMID: 21285249, 23448497). 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.
Ambry Genetics RCV000116096 SCV000183829 pathogenic Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing The c.3113G>A pathogenic mutation (also known as p.W1038*), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3113. This changes the amino acid from a tryptophan to a stop codon within coding exon 10. This change occurs in the last base pair of coding exon 10, and has been shown to generate three aberrant mRNA isoforms: one with complete skipping of exon 10 (deletion of 117 bp), another which uses an alternative splice site within exon 10 (out-of-frame deletion of 31 bp), and one which results in an immediate stop at codon W1038 (p.W1038*) (Casadei S et al. Cancer Res. 2011 Mar;71:2222-9). In another study, the authors identified two of the three transcripts reported in Casadei et al., which included the alternate transcripts with complete skipping of exon 10 and the 31 bp deletion in exon 10 (Teo ZL et al. Breast Cancer Res. 2013 Feb;15:R17). In addition, this mutation has been identified in multiple early-onset breast cancer probands with significant breast cancer family histories (Hartley T et al. Hered Cancer Clin Pract. 2014;12:19; Teo ZL et al. Fam. Cancer. 2013 Dec;12:587-95; Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Wong MW et al. Breast Cancer Res. Treat. 2011 Jun;127:853-9; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Ding YC et al. Fam. Cancer. 2018 Apr;17:187-195). This alteration has also been reported in a kindred with at least two family members affected with pancreatic cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000212822 SCV000225072 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000116096 SCV000266105 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114591 SCV000267971 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Color Health, Inc RCV000116096 SCV000292142 pathogenic Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing This variant causes a nonsense mutation in exon 10 and is also predicted to disrupt splicing at the intron 10 splice donor site in the PALB2 gene. RNA studies have reported that this variant causes splicing defects resulting in-frame partial deletion of the WD40 protein domain or premature termination, while transcript without splicing defect has a nonsense mutation due to the coding sequence change (PMID: 21285249, 31843900). This variant has been observed in over a dozen individuals affected with early-onset breast cancer with positive history of breast and other cancers (PMID: 17200668, 21182766, 21285249, 22241545, 23471749, 25225577, 28864920), an individual affected with familial pancreatic cancer (PMID: 25356972), and in two ovarian cancer cases and two unaffected controls (PMID: 26315354). This variant also has been shown to segregate with breast cancer in families (PMID: 21182766, 26534844). The carriers in one study share a common haplotype (PMID: 21285249) and this variant is thought to be a founder mutation in families of English ancestry. This variant has been identified in 17/282756 chromosomes in the general population by the Genome Aggregation Database (gnomAD), predominantly in non-Finnish Europeans and also in African-Americans. Loss of PALB2 function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
Counsyl RCV000114591 SCV000488411 pathogenic Familial cancer of breast 2016-03-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212822 SCV000601775 pathogenic not provided 2019-09-30 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588093 SCV000699583 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-08 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000114591 SCV000840027 pathogenic Familial cancer of breast 2017-04-03 criteria provided, single submitter clinical testing This c.3113G>A (p.Trp1038*) variant has previously been reported in 16 (out of 4,178 total) patients with breast cancer [PMID 17200668, 21285249, 25575445, 23448497, 26283626, 21409391, 23471749]. The cumulative risk for carrier of this variant was estimated as 91% by age 70 with a median age of onset of 42 years old reported in an Australian population [PMID 23471749]. This c.3113G>A is located in exon 10 of the PALB2 gene at the exon/intron junction with intron 10. Transcripts analysis showed that this variant not only produces a stop codon at amino acid position 1038 but also produces two additional PALB2 transcripts including an alternative splicing and a complete deletion of exon 10, all three leading to a loss of function of the protein [PMID 23471749]. The c.3113G>A (p.Trp1038*) variant has been observed in two Europeans and one African individual at the heterozygous state in the ExAC population database ( It is thus interpreted as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778460 SCV000914711 pathogenic PALB2-Related Disorders 2018-09-19 criteria provided, single submitter clinical testing The PALB2 c.3113G>A (p.Trp1038Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the c.3113G>A (p.Trp1038Ter) variant has been identified in a heterozygous state in at least 21 probands from 13 unrelated families (Rahman et al. 2007; Southey et al. 2010; Teo et al. 2013; Hartley et al. 2014). Affected individuals were found to have a variety of cancers including breast, ovarian, and pancreatic. The p.Trp1038Ter variant was absent from 1724 healthy control subjects and is reported at a frequency of 0.000125 in the African population of the Genome Aggregation Database. Experimental studies on RNA isolated from patient derived lymphoblastoid cell lines have shown that the p.Trp1038Ter variant caused altered splicing (Casadei et al. 2011; Teo et al. 2013). Although this variant has not been reported in any probands with Fanconi anemia, it is known that PALB2 heterozygous variants can also confer carrier status for Fanconi anemia. Due to the potential impact of stop-gained variants and the evidence from the literature, this variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Academic Department of Medical Genetics, University of Cambridge RCV000116096 SCV000992220 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.
OMIM RCV000144703 SCV000190693 risk factor Breast cancer, susceptibility to 2013-02-28 no assertion criteria provided literature only
Pathway Genomics RCV000114591 SCV000207350 pathogenic Familial cancer of breast 2014-11-06 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000212822 SCV001193348 pathogenic not provided 2019-09-30 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: James Whitworth, kConFab - Heather Thorne, Marc Tischkowitz.
King Laboratory,University of Washington RCV001171469 SCV001251380 pathogenic Familial cancer of breast; Hereditary cancer-predisposing syndrome 2019-09-01 no assertion criteria provided research
GenomeConnect - Invitae Patient Insights Network RCV001535480 SCV001749413 not provided Fanconi anemia, complementation group N; Pancreatic cancer 3; Malignant tumor of breast no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 04-13-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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