ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2509G>A (p.Glu837Lys)

gnomAD frequency: 0.00010  dbSNP: rs587778587
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656936 SCV000149996 likely benign not provided 2020-02-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26411315, 29190888, 24728327, 24755471, 27783279, 24163242, 28796317, 29338689)
Ambry Genetics RCV000116087 SCV000172832 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-17 criteria provided, single submitter clinical testing The p.E837K variant (also known as c.2509G>A), located in coding exon 5 of the PALB2 gene, results from a G to A substitution at nucleotide position 2509. The glutamic acid at codon 837 is replaced by lysine, an amino acid with similar properties. This variant has been detected in Japanese and Korean individuals with hereditary breast and ovarian cancer and in a Korean patient with Beckwith-Wiedemann syndrome <span style="background-color:rgb(255, 255, 255); font-family:sans-serif,arial,verdana,trebuchet ms">(Kim H et al. Breast Cancer Res. Treat., 2017 01;161:95-102; Nakagomi H et al. Int. J. Clin. Oncol., 2016 Apr;21:270-275; Sato K et al. Cancer Sci., 2017 Nov;108:2287-2294; Kim SY et al. Oncotarget, 2017 Nov;8:91950-91957; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Shin HC et al. Cancer Res Treat, 2020 Feb;:). One of these studies found no significant difference in frequency between these patients and healthy Japanese individuals registered in the Human Genome Variation Database (Sato K et al. Cancer Sci., 2017 Nov;108:2287-2294;). Another study identified this variant in 1/62 healthy East Asian individuals (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000989556 SCV000290839 likely benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000318539 SCV000396094 uncertain significance Fanconi anemia complementation group N 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services,Illumina RCV000116087 SCV000396095 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116087 SCV000902868 likely benign Hereditary cancer-predisposing syndrome 2016-04-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121758 SCV000917952 likely benign not specified 2020-09-04 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2509G>A (p.Glu837Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250516 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. Specifically, the variant allele was detected at a frequency of 0.0042 within Korean controls (gnomAD) and at a frequency range of 0.0058-0.0069 within Japanese controls (Momozawa_2018 and HGVD and jMorp databases). Therefore, the observed variant frequency within East Asian control individuals is at least 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Though c.2509G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Nakagomi 2016, Kim 2017, Sato 2017, Shin_2020) and in a patient with Beckwith-Wiedemann syndrome and hepatoblastoma (Kim 2017), these patients were all of East Asian origin. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (BRCA1 c.188T>A, p.L63X; PTEN c.697C>T, p.Arg233X; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000989556 SCV001140004 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030647 SCV001193677 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798359 SCV002043595 uncertain significance Breast and/or ovarian cancer 2020-05-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656936 SCV002046129 uncertain significance not provided 2021-01-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000121758 SCV002067601 uncertain significance not specified 2018-11-26 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000116087 SCV002530705 likely benign Hereditary cancer-predisposing syndrome 2021-10-15 criteria provided, single submitter curation
ITMI RCV000121758 SCV000085956 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000116087 SCV000805277 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000121758 SCV001193239 benign not specified 2018-10-10 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356207 SCV001551313 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Glu837Lys variant was identified in 5 of 780 proband chromosomes (frequency: 0.0064) from individuals or families with breast cancer and was present in 1 of 124 control chromosomes (frequency: 0.008) from healthy individuals (Kim 2017, Nakagomi 2016). The variant was also identified in dbSNP (ID: rs587778587) as “With Pathogenic, other allele”, ClinVar (6x, as likely benign by Invitae, Ilummina, uncertain significance by Ambry Genetics, GeneDx, and ITMI), Clinvitae (4x), Cosmic (1x, large intestine, prostate, carcinoma), databases. The variant was not identified in MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 30 of 276582 chromosomes at a frequency of 0.000108 in the following populations: African in 6 of 25030 chromosomes (freq. 0.00024), East Asian in 24 of 18870 chromosomes (freq. 0.0013), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic BRCA2 variant (c.4042delT, p.Cys1348ValfsX26) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.Glu837Lys variant does not have clinical significance The p.Glu837Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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