ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3247G>A (p.Glu1083Lys) (rs747785029)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196986 SCV000255099 uncertain significance Familial cancer of breast 2019-09-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1083 of the PALB2 protein (p.Glu1083Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs747785029, ExAC 0.009%). This variant has been reported in the literature in an individual affected with head and neck squamous cell cancer (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 216753). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000196986 SCV000488001 uncertain significance Familial cancer of breast 2015-12-10 criteria provided, single submitter clinical testing
GeneDx RCV000480697 SCV000566312 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3247G>A at the cDNA level, p.Glu1083Lys (E1083K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant was observed in an individual with head and neck squamous cell carcinoma (Chandrasekharappa 2017). PALB2 Glu1083Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in within the regions of interaction with BRCA2, RAD51, POLH, and POLH DNA synthesis stimulation (Oliver 2009, Buisson 2010, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PALB2 Glu1083Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574156 SCV000663279 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-19 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
Color RCV000574156 SCV000686018 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764044 SCV000894998 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194139 SCV001363438 uncertain significance not specified 2019-06-03 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3247G>A (p.Glu1083Lys) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3247G>A has been reported in the literature in individuals affected with head and neck squamous cell carcinoma and neuroblastoma (Chandrasekharappa_2017, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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