ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1226A>G (p.Tyr409Cys)

dbSNP: rs878855097
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000230943 SCV000290804 uncertain significance Familial cancer of breast 2022-10-24 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 409 of the PALB2 protein (p.Tyr409Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 241525). 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. 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.
Mendelics RCV003492015 SCV000839043 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000709387 SCV000905272 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-21 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 409 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has reported that the variant does not impact PALB2 function in a homology-directed repair assay (PMID: 31636395). This variant has been detected 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_010708) and reported in an individual affected with breast cancer and an unaffected individual (PMID: 33811135). This variant has been identified in 1/250868 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985884 SCV001134532 uncertain significance not provided 2019-09-05 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000230943 SCV002512644 uncertain significance Familial cancer of breast 2021-11-22 criteria provided, single submitter clinical testing ACMG classification criteria: PM2 moderate
Ambry Genetics RCV000709387 SCV002664832 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-26 criteria provided, single submitter clinical testing The p.Y409C variant (also known as c.1226A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 1226. The tyrosine at codon 409 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was seen in 1/7840 breast cancer patients and 1/7928 controls in the South East Asian population (Ng PS et al. J Med Genet, 2022 May;59:481-491). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 Mar;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 RCV000230943 SCV005053849 uncertain significance Familial cancer of breast 2024-03-29 criteria provided, single submitter clinical testing

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