ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.149A>C (p.Lys50Thr)

gnomAD frequency: 0.00002  dbSNP: rs763598472
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205692 SCV000260405 likely benign Familial cancer of breast 2020-11-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000221595 SCV000273477 likely benign Hereditary cancer-predisposing syndrome 2019-02-28 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000656934 SCV000292643 uncertain significance not provided 2021-04-28 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30093976, 27443514, 31481248, 26689913, 32255556)
Counsyl RCV000205692 SCV000488846 uncertain significance Familial cancer of breast 2016-07-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656934 SCV000601731 likely benign not provided 2019-10-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000221595 SCV000903305 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-15 criteria provided, single submitter clinical testing This missense variant replaces lysine with threonine at codon 50 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least five individuals affected with breast and/or ovarian, endometrial and pancreatic cancer (PMID: 27443514, 30093976; Color internal data) and glioblastoma multiforme (PMID: 26689913). This variant also has been detected in two individuals affected with breast and/or ovarian cancer with a pathogenic TP53 or BRCA1 variant (PMID: 31481248; Color internal data). A breast cancer case-control meta-analysis has detected this variant in 3/60463 cases and 6/53455 unaffected individuals with OR=0.442 (95%CI 0.111 to 1.768) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011210). This variant has been identified in 1/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236334 SCV000919924 likely benign not specified 2022-07-24 criteria provided, single submitter clinical testing Variant summary: PALB2 c.149A>C (p.Lys50Thr) results in a non-conservative amino acid change in 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 4e-06 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.149A>C has been reported in the literature in an individual affected with glioblastoma multiforme (the cancer genome atlas (TGCA) cohort) (example, Lu_2015), an individual with endometrial carcinoma (example, Ring_2016), a patient with personal history of breast cancer and no family history (example, Chan_2018), and, as a germline variant in a study reporting the archival tumor and blood specimen testing of cancer patients undergoing multigene panel testing (example, Ong_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another germline pathogenic variant has been reported (TP53 c.1015G>T, p.Glu339Ter), providing supporting evidence for a benign role (Ong_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=5). Some submitters cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV000236334 SCV002071985 uncertain significance not specified 2021-11-21 criteria provided, single submitter clinical testing DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.149A>C, in exon 3 that results in an amino acid change, p.Lys50Thr. This sequence change has been previously described in individuals with breast cancer and no family history (PMID: 30093976), endometrial carcinoma (PMID: 27443514) and pancreatic ductal adenocarcinoma (PMID: 32255556). It has also been identified in a tumor specimen of an individual with breast/ovarian cancer, co-occurring with a variant in TP53 (PMID: 31481248). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs763598472). The p.Lys50Thr change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys50Thr substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Lys50Thr change remains unknown at this time.
Sema4,Sema4 RCV000221595 SCV002530619 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-02 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357513 SCV001553003 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Lys50Thr variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, or Zhejiang University Database. The variant was identified in dbSNP (ID: rs763598472) as “With Uncertain Significance allele”, ClinVar (classified as likely benign by Ambry Genetics, and uncertain significance by Invitae, GeneDx, Counsyl and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and in control databases in 1 of 246260 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 1 of 17248 chromosomes (freq: 0.000058), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Lys50 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.