rs515726116
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_024675.4(PALB2):āc.3356T>Cā(p.Leu1119Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1119L) has been classified as Likely benign.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3356T>C | p.Leu1119Pro | missense_variant | 13/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3356T>C | p.Leu1119Pro | missense_variant | 13/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251288Hom.: 1 AF XY: 0.00 AC XY: 0AN XY: 135854
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727180
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 17, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2023 | The p.L1119P variant (also known as c.3356T>C), located in coding exon 13 of the PALB2 gene, results from a T to C substitution at nucleotide position 3356. The leucine at codon 1119 is replaced by proline, an amino acid with similar properties. In a study assessing the contribution of PALB2 mutations to high-risk Jewish breast and ovarian cancer families, this alteration was detected in one Moroccan proband (1/97 cases) and in 0/109 ethnically-matched controls (Catucci I et al. Fam. Cancer. 2012 Sep;11:483-91). This variant was also detected in 1/1240 BRCA1/2-negative individuals recruited from the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54). In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal (Wiltshire T et al. Genet. Med., 2019 Oct, Boonen et al. Nat. Comms. 2019 Nov). In a PARP inhibitor sensitivity assay, this alteration was found to be functionally normal (Boonen et al. Nat. Comms. 2019 Nov, Rodrigue et al. NAR. 2019 Nov). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2022 | This missense variant replaces leucine with proline at codon 1119 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit normal expression and wild type-like homologous recombination activity (PMID: 31757951, 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 22692731, 25575445), as well as in unaffected individuals (Color internal data). This variant has been identified in 4/251288 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2023 | 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; Published functional studies demonstrate intact or reduced homology-directed repair, normal or increased PARP inhibitor sensitivity, decreased BRCA2 binding, moderate cytoplasmic accumulation, and larger RAD51 foci formation (Boonen et al., 2019; Rodrigue et al., 2019; Wiltshire et al., 2020); Observed in individuals with a personal and family history of breast cancer (Catucci et al., 2012; Nguyen-Dumont et al., 2015); This variant is associated with the following publications: (PMID: 25575445, 22692731, 31586400, 31636395, 33195396, 31757951, 24485656, 19609323, 20871615, 33809179) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at