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

dbSNP: rs587776428

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129272	SCV000184032	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-25	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). 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). Further, Hartley et al., reported segregation of this alteration with disease 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211073	SCV000290879	pathogenic	Familial cancer of breast	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the PALB2 gene (p.His1170Phefs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PALB2 protein and extend the protein by 1 additional amino acid residues. This variant is present in population databases (rs587781411, gnomAD 0.1%). This frameshift has been observed in individual(s) with breast, ovarian and prostate cancer and breast cancer (PMID: 24556621, 25099575, 25225577, 26283626, 26314354, 26786923). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3504_3505del. This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Y1183*) have been determined to be pathogenic (PMID: 17200671). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000133490	SCV000322189	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in an extension of the protein, as the last 17 amino acids are replaced with 18 different amino acids, which disrupts a portion of the seventh WD repeat and the critical region required for interaction with RAD51, BRCA2, POLH, and POLH DNA synthesis stimulation (PMID: 19609323, 20871615, 24485656); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26283626, 28825143, 17200671, 26314360, 16793542, 19609323, 26315354, 24556621, 25225577, 25099575, 19423707, 19584259, 24998779, 29431189, 29752822, 32339256, 30982232, 34326862, 34439348, 33804961, 28888541, 32125938, 31428676, 26786923, 31841383, 30254378, 34917121, 20871615, 24485656)
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	2023-06-28	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_MOD,PS4,PM2_SUP_MOD,PP1
Color Diagnostics, LLC DBA Color Health	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.
CeGaT Center for Human Genetics Tuebingen	RCV000133490	SCV001961581	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781465	SCV002016520	pathogenic	Fanconi anemia complementation group N	2020-03-06	criteria provided, single submitter	clinical testing
DASA	RCV004545747	SCV002107149	likely pathogenic	PALB2-related disorder	2022-03-05	criteria provided, single submitter	clinical testing	The c.3507_3508del ;p.(His1170Phefs*?) is a null frameshift variant (NMD) in the PALB2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 140978; 25225577; PMID: 26283626; PMID: 25099575; PMID: 24556621; PMID: 26786923)PS4. The variant is present at low allele frequencies population databases (rs587776428 – gnomAD 0.00006579%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 25225577, 24556621) - PP1_moderate. In summary, the currently available evidence indicates that the variant is likely pathogenic.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225427	SCV002504912	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001781465	SCV002581287	pathogenic	Fanconi anemia complementation group N	2023-03-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000211073	SCV004019688	likely pathogenic	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. Functional studies indicate this variant impacts protein function [PMID: 19423707, 19609323].
Baylor Genetics	RCV000211073	SCV004202784	pathogenic	Familial cancer of breast	2024-03-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760387	SCV005368109	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2024-04-24	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_STR
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002225427	SCV005380454	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-30	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3507_3508delTC (p.His1170PhefsX19) causes a frameshift which results in an extension of the protein. The variant was absent in 251472 control chromosomes. c.3507_3508delTC has been reported in the literature in individuals affected with Hereditary Breast Cancer, Colon cancer and other unspecified cancer (Yang_2020), and segregated with disease in a British family with Breast cancer (Hartley _2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.The following publications have been ascertained in the context of this evaluation (PMID: 25225577, 31841383). ClinVar contains an entry for this variant (Variation ID: 140978). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005016432	SCV005646450	pathogenic	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-01-22	criteria provided, single submitter	clinical testing
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.