rs786203262
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_024675.4(PALB2):āc.2792T>Gā(p.Leu931Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000808 in 1,608,332 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. L931P) 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.2792T>G | p.Leu931Arg | missense_variant | 8/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2792T>G | p.Leu931Arg | missense_variant | 8/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.571A>C | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250918Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135740
GnomAD4 exome AF: 0.00000824 AC: 12AN: 1456170Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 724762
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2023 | - - |
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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 931 of the PALB2 protein (p.Leu931Arg). This variant is present in population databases (rs773831304, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24556926, 25452441, 30086788, 30651582, 33980423). ClinVar contains an entry for this variant (Variation ID: 186840). 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, 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 | MGZ Medical Genetics Center | Jan 12, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 21, 2023 | This missense variant replaces leucine with arginine at codon 931 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the variant protein is fully functional as determined by normal protein expression, homology-directed recombination activity and cell cycle control (PMID: 31636395, 31757951). This variant has been detected in at least 5 individuals affected with breast cancer (PMID: 24556926, 25452441, 30086788, 33471991, 33980423) and individual affected with ovarian cancer (PMID: 30651582) and suspected hereditary breast and ovarian cancer families (PMID: 31159747). This variant has been identified in 4/250918 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 | May 01, 2023 | The p.L931R variant (also known as c.2792T>G), located in coding exon 8 of the PALB2 gene, results from a T to G substitution at nucleotide position 2792. The leucine at codon 931 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Catucci I et al. Genet. Med. 2014 Sep;16(9):688-94; Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Penkert J et al. Breast Cancer Res., 2018 08;20:87; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was also reported in 2/107 Macedonian individuals with a clinical history of hereditary polyposis or hereditary non-polyposis colorectal cancer who underwent multi-gene panel testing (Staninova-Stojovska M et al. Balkan J Med Genet, 2019 Dec;22:5-16). In one homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal (Boonen RACM et al. Nat Commun, 2019 11;10:5296). However, this alteration was found to be functionally inconclusive in another 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2017 | This variant is denoted PALB2 c.2792T>G at the cDNA level, p.Leu931Arg (L931R) at the protein level, and results in the change of a Leucine to an Arginine (CTC>CGC). This variant has been observed in at least three individuals with breast cancer (Catucci 2014, Couch 2015). PALB2 Leu931Arg was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Leu931Arg occurs at a position that is conserved in mammals and is located within the region of interaction with RAD51, BRCA2, and POLH, and the region required for POLH DNA synthesis stimulation (Oliver 2009, Buisson 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Leu931Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | PALB2: BP1, BS3:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 06, 2023 | The frequency of this variant in the general population, 0.000035 (4/113416 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33980423 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 31159747 (2019), 30086788 (2018), 29522266 (2018), 25452441 (2015), 24556926 (2014)), colorectal cancer (PMID: 31942411 (2019)), and healthy individuals (PMIDs: 32658311 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/PALB2)). Functional studies report the variant does not impact PALB2 function (PMIDs: 31636395 (2020), 31757951 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2022 | Variant summary: PALB2 c.2792T>G (p.Leu931Arg) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2792T>G has been reported in the literature in individuals affected with Breast Cancer (Couch_2015, Penkert_2018, Catucci_2014, Solmaz_2021), ovarian cancer (Krivokuca_2019), and colorectal cancer (Staninova-Stojovska_2019), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on homology directed repair and shows no significant impact on PALB2 function (Boonen_2019, Wiltshire_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 02, 2023 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Leu931Arg variant was identified in 3 of 4798 proband chromosomes (frequency: 0.0006) from individuals or families with breast cancer and was not identified in 1568 control chromosomes from healthy individuals (Catucci 2014, Couch 2015, ). The variant was also identified in dbSNP (ID: rs773831304) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color Genomics and one clinical laboratory), and in LOVD 3.0 (2x) databases. The variant was not identified in Cosmic, MutDB, and Zhejiang University databases. The variant was identified in control databases in 3 of 245710 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 3 of 111378 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu931 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at