ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3412G>A (p.Ala1138Thr)

gnomAD frequency: 0.00005  dbSNP: rs577651839
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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 RCV000215508 SCV000275874 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-24 criteria provided, single submitter clinical testing The p.A1138T variant (also known as c.3412G>A), located in coding exon 13 of the PALB2 gene, results from a G to A substitution at nucleotide position 3412. The alanine at codon 1138 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000686283 SCV000813795 uncertain significance Familial cancer of breast 2025-01-26 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1138 of the PALB2 protein (p.Ala1138Thr). This variant is present in population databases (rs577651839, gnomAD 0.01%). This missense change has been observed in individual(s) with prostate cancer (PMID: 37436117). ClinVar contains an entry for this variant (Variation ID: 231889). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759188 SCV000888375 uncertain significance not provided 2023-12-28 criteria provided, single submitter clinical testing The PALB2 c.3412G>A (p.Ala1138Thr) variant has been reported in the published literature in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.00014 (5/34592 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4 RCV000215508 SCV002531177 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-20 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000686283 SCV004189554 likely benign Familial cancer of breast 2023-11-13 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics RCV000686283 SCV004202627 uncertain significance Familial cancer of breast 2024-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000759188 SCV005325614 uncertain significance not provided 2024-02-11 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 33471991)
Fulgent Genetics, Fulgent Genetics RCV005016592 SCV005646455 uncertain significance Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5 2024-06-21 criteria provided, single submitter clinical testing

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