ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1419A>C (p.Pro473=)

gnomAD frequency: 0.00255  dbSNP: rs62625275
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212794 SCV000170870 benign not specified 2013-12-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000127309 SCV000212819 likely benign Hereditary cancer-predisposing syndrome 2014-06-18 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000114473 SCV000261726 benign Familial cancer of breast 2021-12-11 criteria provided, single submitter clinical testing
Counsyl RCV000114473 SCV000487912 likely benign Familial cancer of breast 2015-12-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212794 SCV000596215 likely benign not specified 2016-01-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000127309 SCV000685877 benign Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000585974 SCV000699533 benign not provided 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The PALB2 c.1419A>C (p.Pro473Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing and alteration to an ESE binding site, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC with an allele frequency of 129/121282 (1/939, 2 homozygotes), predominantly in the African cohort, 121/10362 (1/85, 2 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PALB2 variant of 1/6397. Therefore, suggesting the variant is a common polymorphism found in population(s) of African origin. In addition, multiple reputable clinical laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into considearation, the variant of interest has been classified as Benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000127309 SCV000747821 likely benign Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212794 SCV000807075 benign not specified 2017-06-20 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225294 SCV002504938 likely benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000127309 SCV000805275 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000114473 SCV001193100 benign Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358133 SCV001553793 benign Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Pro473= variant was identified in 4 of 3246 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and was not identified in 2082 control chromosomes from healthy individuals (Damiola 2015, Ding 2011, Hellebrand 2011, Sauty de Chalon 2010). The variant was also identified in the following databases: dbSNP (ID: rs62625275), ClinVar (classified as benign by GeneDx, Invitae, Color Genomics, Laboratory Corporation of America; as likely benign by Ambry Genetics, Counsyl, GSLUOC, PALB2 database), Clinvitae (conflicting interpretations of pathogenicity), Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 270 of 276902 chromosomes (2 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 242 of 24034 chromosomes (freq: 0.01), “Other” in 1 of 6464 chromosomes (freq: 0.0002), Latino in 21 of 34414 chromosomes (freq: 0.001), European in 4 of 126400 chromosomes (freq: 0.00003), and South Asian in 2 of 30782 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Pro473= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000212794 SCV001800038 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000212794 SCV001906330 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000212794 SCV001926624 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000585974 SCV001957996 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212794 SCV002551678 benign not specified 2021-08-27 no assertion criteria provided clinical testing

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