Submissions for variant NM_024675.4(PALB2):c.3191A>G (p.Tyr1064Cys)

dbSNP: rs730881893

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160850	SCV000211528	uncertain significance	not provided	2023-11-12	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and ovarian cancer (PMID: 37686625, 26898890); 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: 26898890, 24485656, 19609323, 20871615, 31636395, 31757951, 37686625)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467780	SCV000550674	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1064 of the PALB2 protein (p.Tyr1064Cys). This variant is present in population databases (rs730881893, 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: 182773). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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.
Color Diagnostics, LLC DBA Color Health	RCV000774624	SCV000908459	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1064 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies reported that this variant does not impact PALB2 in homology-directed DNA repair, cisplatin and PARP inhibitor sensitivity, and cell cycle progression assays (PMID: 31636395, 31757951). This variant has been reported in an individual affected with breast, ovarian, pancreatic or prostate cancer (PMID: 37686625), and in a prostate cancer case-control study in 1/7636 cases and absent in 12366 unaffected individuals (PMID: 31214711) and in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010670). This variant has been identified in 3/251170 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.
Ambry Genetics	RCV000774624	SCV001180394	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-22	criteria provided, single submitter	clinical testing	The p.Y1064C variant (also known as c.3191A>G), located in coding exon 11 of the PALB2 gene, results from an A to G substitution at nucleotide position 3191. The tyrosine at codon 1064 is replaced by cysteine, an amino acid with highly dissimilar properties. In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal. In a PARP inhibitor sensitivity assay, this alteration was found to be functionally normal. In a RAD51 foci assay this alteration was found to be functionally normal. (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This alteration was found to be functionally inconclusive in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000467780	SCV004202196	uncertain significance	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing