ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3507_3508del (p.His1170fs) (rs587776428)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129272 SCV000184032 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-10 criteria provided, single submitter clinical testing The c.3507_3508delTC variant, located in coding exon 13 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 3507 to 3508, causing a translational frameshift with a predicted alternate stop codon (p.H1170Ffs*19). This alteration occurs at the 3' terminus of the PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, alters the last 17 amino acids of the protein and results in the elongation of the protein by one amino acid. However, these 3' amino acids are part of the functionally critical WD40 domain that is necessary for PALB2 function, stability, and interaction with BRCA2 (Oliver AW et al. EMBO Rep., 2009 Sep;10:990-6). <span style="background-color: initial;">This alteration has also been reported in multiple individuals with personal and/or family history suggestive of hereditary breast, ovarian, or prostate cancer (Leongamornlert D et al. Br J Cancer. 2014 Mar 18;110(6):1663-72; Hartley T et al. Hered Cancer Clin Pract. 2014 Aug 28;12(1):19; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11); Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Zhang K et al. Breast Cancer Res. Treat. 2017 Dec;166:865-873; Lee JEA et al. J. Pathol. 2018 May;245:53-60; Li JY et al. Int. J. Cancer. 2019 01;144:281-289; Rowley SM et al. Genet. Med., 2019 04;21:913-922; Yadav S et al. J. Clin. Oncol., 2020 May;38:1409-1418<span style="background-color: initial;">). Further, Hartley et al., reported segregation of this alteration with disease <span style="background-color: initial;">in 4 out of 5 individuals from one family. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000211073 SCV000267975 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Invitae RCV000211073 SCV000290879 pathogenic Familial cancer of breast 2020-10-05 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 13 of the PALB2 mRNA (c.3507_3508delTC), causing a frameshift at codon 1170. This results in replacing the C-terminal 17 amino acids with 18 different amino acids (p.His1170Phefs*19), but is not anticipated to result in nonsense mediated decay of the PALB2 mRNA. This variant has been reported to segregate with breast cancer in a single family (PMID: 25225577), and in unrelated individuals affected with breast, ovarian and prostate cancer (PMID: 26283626, 25099575, 26314354, 24556621, 26786923). This variant is also known as c.3504_3505del in the literature (PMID: 25099575). ClinVar contains an entry for this variant (Variation ID: 140978). This variant disrupts the WD40-repeat domain of the PALB2 protein, which is important for proper PALB2 protein function (PMID: 16793542, 19423707). Although functional studies have not been performed for this particular variant, a downstream truncation (p.Tyr1183*) that deletes only the final 4 amino acid residues results in a nonfunctional PALB2 protein (PMID: 17200671). This suggests that disruption of this region of the PALB2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000133490 SCV000322189 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing This deletion of two nucleotides in PALB2 is denoted c.3507_3508delTC at the cDNA level and p.His1170PhefsX19 (H1170FfsX19) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACTC[delTC]ATTT. The deletion causes a frameshift which changes a Histidine to a Phenylalanine at codon 1170 in the last exon of the gene, and results in an extension of the protein. The last 17 correct amino acids are replaced by 18 incorrect ones, disrupting a portion of the seventh WD repeat and a region that interacts with RAD51, BRCA2, and POLH (UniProt, Oliver 2009, Buisson 2010, Buisson 2014). PALB2 c.3507_3508delTC, also reported as c.3504_3505del, has been observed in individuals with a personal and/or family history of breast, ovarian, and prostate cancers, and was absent in studied controls (Antoniou 2014, Leongamornlert 2014, Hartley 2014, Thompson 2015, Ramus 2015, Zhang 2017, Lee 2018). Based on the currently available information, we consider PALB2 c.3507_3508delTC to be pathogenic.
Counsyl RCV000211073 SCV000677794 likely pathogenic Familial cancer of breast 2017-05-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000211073 SCV001251423 pathogenic Familial cancer of breast 2019-10-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129272 SCV001348382 pathogenic Hereditary cancer-predisposing syndrome 2020-12-07 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides in the last coding exon 13 of the PALB2 gene, substituting the last 17 amino acids of the protein with 18 different amino acids. This variant may also be known as c.3504_3505del. The variant impacts the C-terminus of the WD40 repeats domain, a known functional domain (PMID: 16793542, 19423707). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals with personal and/or family history of breast and ovarian cancer (PMID: 25099575, 25225577, 26283626, 26315354, 26786923, 29752822, 29431189, 28825143) and prostate cancer (PMID: 24556621), including one family in which the variant segregates with three first-degree relatives with early-onset or bilateral breast cancer (PMID: 25225577). This variant has been identified in 1/31326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
SNPedia RCV000133490 SCV000188564 pathogenic not provided no assertion criteria provided not provided Converted during submission to Pathogenic.
Leiden Open Variation Database RCV000211073 SCV001193423 pathogenic Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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