rs45464500
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_024675.4(PALB2):āc.2840T>Cā(p.Leu947Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,574 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L947F) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2840T>C | p.Leu947Ser | missense_variant | 9/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2840T>C | p.Leu947Ser | missense_variant | 9/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.420-775A>G | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152054Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251104Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135752
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461520Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34AN XY: 727064
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74266
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 947 of the PALB2 protein (p.Leu947Ser). This variant is present in population databases (rs45464500, gnomAD 0.006%). This missense change has been observed in individual(s) with pancreatic cancer and breast cancer (PMID: 28767289, 32206661). ClinVar contains an entry for this variant (Variation ID: 241553). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31586400, 31636395, 31757951). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jun 20, 2024 | 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]. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2016 | Variant summary: The PALB2 c.2840T>C (p.Leu947Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 6/118288 control chromosomes at a frequency of 0.0000507, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). The variant has not, to our knowledge, been reported in affected individuals in the literature. However, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2023 | 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: 28779002, 28767289, 31586400, 31757951, 31636395, 32209438, 32185139, 32206661, 33195396, 34092963, 32659497, 33169439, 17200668) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2023 | This missense variant replaces leucine with serine at codon 947 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and functio. Functional studies have found that this variant partially impacts PALB2 activities in homology-directed DNA repair, PARP inhibitor sensitivity, damage-induced RAD51 foci formation, PALB2 nuclear localization and BRCA2 interaction (PMID: 31586400, 31757951, 31636395). This variant has been detected in a breast cancer case-control meta-analysis in 5/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010687) and in an individual affected with pancreatic cancer (PMID: 32659497). This variant also has been detected in one individual each affected with pancreatic or ovarian cancer who also carries a pathogenic ATM covariant (PMID: 28767289, 32206661). This variant has been identified in 7/251104 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 17, 2022 | The p.L947S variant (also known as c.2840T>C), located in coding exon 9 of the PALB2 gene, results from a T to C substitution at nucleotide position 2840. The leucine at codon 947 is replaced by serine, an amino acid with dissimilar properties. This alteration showed intermediate activity in multiple functional assays including PARP inhibitor sensitivity, RAD51 foci formation, and homology-directed DNA repair (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677; Wiltshire T et al. Genet. Med., 2020 03;22:622-632) and was deficient in binding BRCA2 (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). In another functional study, this alteration showed abnormal activity in homology-directed DNA repair and PARP inhibitor sensitivity assays (Boonen RACM et al. Nat Commun, 2019 11;10:5296). In one study, this alteration was identified in 0/923 familial breast cancer cases and 1/1084 controls (Rahman N et al. Nat. Genet., 2007 Feb;39:165-7). This alteration was also identified in a cohort of patients with pancreatic cancer or other periampullary neoplasms tested for hereditary cancer risk via a multi-gene panel, specifically in a 77 year old male with pancreatic ductal adenocarcinoma who also had a pathogenic missense ATM alteration (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). In addition, this alteration was identified in a woman with a history of DCIS and ovarian cancer who also had a pathogenic ATM gross deletion (Carbajal-Mamani SL et al. Obstet Gynecol Sci, 2020 Mar;63:205-208). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). 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. - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at