ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1178A>G (p.Lys393Arg)

gnomAD frequency: 0.00001  dbSNP: rs765898856
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000204310 SCV000260202 uncertain significance Familial cancer of breast 2024-05-14 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 393 of the PALB2 protein (p.Lys393Arg). This variant is present in population databases (rs765898856, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 219990). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV001010149 SCV001170303 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-09 criteria provided, single submitter clinical testing The p.K393R variant (also known as c.1178A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 1178. The lysine at codon 393 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002494523 SCV002785729 uncertain significance Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3 2021-12-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV000204310 SCV004202124 uncertain significance Familial cancer of breast 2023-08-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488460 SCV004241504 uncertain significance not specified 2023-12-14 criteria provided, single submitter clinical testing Variant summary: PALB2 c.1178A>G (p.Lys393Arg) 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 4e-06 in 250980 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1178A>G has been reported in the literature in individuals affected with ovarian cancer and pancreatic/breast cancer (e.g. Ramus_2015, Dudley_2018). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29360161, 26315354). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV004767150 SCV005375815 uncertain significance not provided 2023-11-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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