ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.1756G>A (p.Asp586Asn) (rs587781954)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130326 SCV000185176 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000411835 SCV000488987 uncertain significance Familial cancer of breast 2016-07-29 criteria provided, single submitter clinical testing
Invitae RCV000411835 SCV000550647 uncertain significance Familial cancer of breast 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 586 of the PALB2 protein (p.Asp586Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs587781954, ExAC 0.005%). This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141709). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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.
GeneDx RCV000481375 SCV000565350 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.1756G>A at the cDNA level, p.Asp586Asn (D586N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has been observed in at least one individual with breast cancer (Tung 2015). PALB2 Asp586Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PALB2 Asp586Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764051 SCV000895005 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000130326 SCV000903125 likely benign Hereditary cancer-predisposing syndrome 2015-06-03 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000411835 SCV001193152 uncertain significance Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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