ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2773G>C (p.Val925Leu) (rs180177125)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129279 SCV000184039 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000114558 SCV000259312 uncertain significance Familial cancer of breast 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 925 of the PALB2 protein (p.Val925Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs180177125, ExAC 0.005%). This variant has been reported in individuals affected with breast cancer and prostate cancer (PMID: 18288683, 19763884, 29052111). ClinVar contains an entry for this variant (Variation ID: 126681). 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 leucine 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 RCV000235847 SCV000292755 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2773G>C at the cDNA level, p.Val925Leu (V925L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). This variant has been observed in several individuals with breast or ovarian cancer and in an individual with a history of prostate cancer whose affected brother was also positive for this variant (Tischkowitz 2008, Papi 2010, Maxwell 2016, Myszka 2017). PALB2 Val925Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the WD2 repeat, the region of interaction with POLH, RAD51 and BRCA2, and the region required for POLH DNA synthesis stimulation (Oliver 2009, Buisson 2010, Buisson 2014, UniProt). 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 Val925Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000114558 SCV000489581 uncertain significance Familial cancer of breast 2016-10-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515304 SCV000611497 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3; Tracheoesophageal fistula 2017-05-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764047 SCV000895001 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000129279 SCV000902881 likely benign Hereditary cancer-predisposing syndrome 2015-05-29 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000235847 SCV001193286 uncertain significance not provided 2019-09-30 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz, Melissa DeRycke.

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