ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)

gnomAD frequency: 0.00041  dbSNP: rs183489969
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130354 SCV000185205 likely benign Hereditary cancer-predisposing syndrome 2019-06-27 criteria provided, single submitter clinical testing No disease association in appropriately sized case-control study(ies);Subpopulation frequency in support of benign classification
GeneDx RCV000858970 SCV000211527 likely benign not provided 2020-10-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28825143, 21285249, 22241545, 25575445, 26283626, 23977390, 25356972, 26489409, 26692951, 27783279, 26411315, 27616075, 28580595, 27099641, 26757417, 28664506, 31159747, 31586400, 32566746, 32426482)
Invitae RCV000114588 SCV000253601 benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114588 SCV000268021 uncertain significance Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Illumina Laboratory Services,Illumina RCV000286032 SCV000396076 likely benign Fanconi anemia complementation group N 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services,Illumina RCV000130354 SCV000396077 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212821 SCV000699582 benign not specified 2019-03-28 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3054G>C (p.Glu1018Asp) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 281404 control chromosomes, predominantly at a frequency of 0.0052 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3054G>C has been reported in the literature predominantly in individuals of East Asian origin affected with Hereditary Breast and Ovarian Cancer (Casadei_2011, Tischkowitz_2012, Thompson_2015, Phuah_2013, Nguyen_Dumont_2015, Kraus_2017, Li_2015, Yang_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing database (BRCA1 c.2728delC, p.Gln910fsX90), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four of these classified the variant as Benign/Likely benign and three classified it as a VUS. Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA RCV000130354 SCV000822112 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000130354 SCV000902643 benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000858970 SCV001134550 likely benign not provided 2020-04-20 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030645 SCV001193675 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000858970 SCV001474440 likely benign not provided 2019-09-04 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212821 SCV002067808 likely benign not specified 2021-01-12 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000130354 SCV002530749 likely benign Hereditary cancer-predisposing syndrome 2020-12-31 criteria provided, single submitter curation
Leiden Open Variation Database RCV000114588 SCV001193337 likely benign 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356371 SCV001551521 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Glu1018Asp variant was identified in 6 of 3322 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Kim 2016, Li 2015, Nakagomi 2016, Phuah 2013, Thompson 2015). The variant was also identified in the following databases: dbSNP (ID: rs183489969) as With Likely benign, Uncertain significance, other allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, CGLPMCC; classified as likely benign by Illumina; classified as Benign by Invitae), Clinvitae (conflicting interpretations of pathogenicity), Cosmic (none (score 0.69)), MutDB , LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 102 of 277208 chromosomes at a frequency of 0.000368 in the following populations: other in 3 of 6464 chromosomes (freq. 0.00046), European in 1 of 126704 chromosomes (freq. 0.000008), East Asian in 98 of 18868 chromosomes (freq. 0.005), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Glu1018 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant is located with the WD40-repeat-containing domain. The variant p.Glu1018Asp was listed as a rare missense variant in a study of 155 Japanese patients with breast and/or ovarian cancers; in this family, the family history of 25 relatives was available but none were reported with breast and/or ovarian cancer (Nakagomi 2016). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212821 SCV002551637 likely benign not specified 2022-05-06 no assertion criteria provided clinical testing

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