ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr)

dbSNP: rs759795184
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV001030371 SCV003915568 uncertain significance Familial cancer of breast 2023-04-05 reviewed by expert panel curation The c.3049G>A (p.Ala1017Thr) variant in PALB2 is a missense variant predicted to cause a substitution of alanine by threonine at amino acid 1017 (p.Ala1017Thr). This variant has a minor allele frequency in gnomAD v2.1.1 of 0.00003 in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in a protein assay (PMID: 31586400); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP (BP1)
Color Diagnostics, LLC DBA Color Health RCV001180325 SCV001345228 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-21 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1017 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant does not impact PALB2 binding to BRCA2 in a mammalian two-hybrid assay (PMID: 31586400). This variant has been reported in an individual affected with breast cancer (PMID: 23977390). This variant has been identified in 1/251448 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001030371 SCV001398871 uncertain significance Familial cancer of breast 2023-04-23 criteria provided, single submitter clinical testing 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31586400). 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 expected to disrupt PALB2 protein function. ClinVar contains an entry for this variant (Variation ID: 830187). This missense change has been observed in individual(s) with breast cancer (PMID: 23977390). This variant is present in population databases (rs759795184, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1017 of the PALB2 protein (p.Ala1017Thr).
Ambry Genetics RCV001180325 SCV002754109 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-24 criteria provided, single submitter clinical testing The p.A1017T variant (also known as c.3049G>A), located in coding exon 10 of the PALB2 gene, results from a G to A substitution at nucleotide position 3049. The alanine at codon 1017 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in in 1/222 Asian women with breast cancer, all of whom had significant family history of breast and other cancers (Phuah SY et al. PLoS ONE, 2013 Aug;8:e73638). In a PARP inhibitor sensitivity assay, this alteration was found to have normal activity. In a BRCA2 binding assay, this alteration was found to have normal activity (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). 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.
Neuberg Centre For Genomic Medicine, NCGM RCV003339428 SCV004047472 uncertain significance Fanconi anemia complementation group N criteria provided, single submitter clinical testing The missense variant c.3049G>A (p.Ala1017Thr) in PALB2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ala1017Thr variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003977% is reported in gnomAD . The amino acid Ala at position 1017 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala1017Thr in PALB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Baylor Genetics RCV001030371 SCV005055025 uncertain significance Familial cancer of breast 2023-12-11 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV001030371 SCV001193334 likely benign 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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