ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.758dup (p.Ser254fs) (rs515726126)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129208 SCV000185051 pathogenic Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing The c.758dupT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a duplication of T at nucleotide position 758, causing a translational frameshift with a predicted alternate stop codon (p.S254Ifs*3). This mutation has previously been reported in multiple individuals affected with breast cancer (Zheng Y et al. Cancer. 2012 Mar;118:1362-70; Pern F et al. PLoS ONE. 2012 Oct;7:e47993; Wong-Brown MW et al. Int. J. Cancer. 2014 Jan;134:301-5; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Lerner-Ellis J et al. Breast Cancer Res. Treat. 2017 04;162:591-596; Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9). 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.
GeneDx RCV000212780 SCV000211484 pathogenic not provided 2018-12-30 criteria provided, single submitter clinical testing This pathogenic duplication of one nucleotide in PALB2 is denoted PALB2 c.758dupT at the cDNA level and p.Ser254IlefsX3 (S254IfsX3) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTC[dupT]ATCA. The duplication causes a frameshift, which changes a Serine to an Isoleucine at codon 254, and creates a premature stop codon at position 3 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.758dupT has been reported in association with familial breast cancer, including triple negative and bilateral disease, and has also been identified in individuals with melanoma and ovarian cancer (Pern 2012, Zheng 2012, Kanchi 2014, Wong-Brown 2014, Churpek 2015, Thompson 2015). We consider this variant to be pathogenic.
Invitae RCV000114661 SCV000253947 pathogenic Familial cancer of breast 2020-10-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser254Ilefs*3) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs756660214, ExAC 0.01%). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 21932393, 22692731, 23110154, 26283626, 23824750, 24448499, 24870022). ClinVar contains an entry for this variant (Variation ID: 126769). 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.
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114661 SCV000267963 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Counsyl RCV000114661 SCV000488259 pathogenic Familial cancer of breast 2016-02-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212780 SCV000601797 pathogenic not provided 2017-07-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129208 SCV000686074 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001293421 SCV000919931 pathogenic Hereditary breast and ovarian cancer syndrome 2021-02-12 criteria provided, single submitter clinical testing Variant summary: PALB2 c.758dupT (p.Ser254IlefsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251366 control chromosomes. c.758dupT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Zheng_2012, Pern_2012, Wong-Brown_2014, Lerner-Ellis_2017, Carter_2018). 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. Nine other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286200 SCV001472732 pathogenic none provided 2020-07-24 criteria provided, single submitter clinical testing The PALB2 c.758dupT; p.Ser254IlefsTer3 variant (rs515726126) is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Carter 2018, Lerner-Ellis 2017, Pern 2012, Thompson 2015, Wong-Brown 2014, Zheng 2012). This variant is found on only six chromosomes (6/251366 alleles) in the Genome Aggregation Database. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Carter et al. Germline Pathogenic Variants Identified in Women With Ovarian Tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. Lerner-Ellis et al. A High Frequency of PALB2 Mutations in Jamaican Patients With Breast Cancer. Breast Cancer Res Treat. 2017 Apr;162(3):591-596. Pern et al. Mutation Analysis of BRCA1, BRCA2, PALB2 and BRD7 in a Hospital-Based Series of German Patients With Triple-Negative Breast Cancer. PLoS One. 2012;7(10):e47993. Thompson ER et al. Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls. Breast Cancer Res. 2015;17(1):111. Wong-Brown MW et al. Low prevalence of germline PALB2 mutations in Australian triple-negative breast cancer. Int J Cancer. 2014;134(2):301-305. Zheng et al. Novel Germline PALB2 Truncating Mutations in African American Breast Cancer Patients. Cancer. 2012 Mar 1;118(5):1362-70.
Leiden Open Variation Database RCV000114661 SCV001193014 pathogenic Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212780 SCV001739947 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000212780 SCV001807019 pathogenic not provided no assertion criteria provided clinical testing

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