rs61756146
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_024675.4(PALB2):c.2978C>T(p.Thr993Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. T993A) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2978C>T | p.Thr993Met | missense_variant | 9/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2978C>T | p.Thr993Met | missense_variant | 9/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.420-913G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251460Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727228
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a slight decrease in homologous recombination efficiency (Ng 2021); Observed in individuals with breast cancer or cervical rhabdomyosarcoma (Cowan 2018, Ng 2021); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 33811135, 30014022) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 21, 2022 | The frequency of this variant in the general population, 0.00002 (5/251460 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. This variant has reported in individuals with breast cancer (PMID: 33811135 (2022), 33471991 (2021)) as well as in unaffected healthy individuals ((PMID: 33811135 (2022), 33471991 (2021)). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
Familial cancer of breast Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 18, 2023 | 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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 993 of the PALB2 protein (p.Thr993Met). This variant is present in population databases (rs61756146, 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: 232056). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2023 | The p.T993M variant (also known as c.2978C>T), located in coding exon 9 of the PALB2 gene, results from a C to T substitution at nucleotide position 2978. The threonine at codon 993 is replaced by methionine, an amino acid with similar properties. This alteration has 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). In another study, this variant was reported in 5/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med, 2021 02;384:428-439). This variant was detected in 4/7840 breast cancer cases and 1/7929 healthy controls from Southeast Asia (Ng PS et al. J Med Genet, 2022 May;59:481-491), and was detected in 0/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 1/1189 controls. (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This alteration was reported in a 24-year-old female with a history of two primary cervical embryonal rhabdomyosarcomas and ovarian Sertoli-Leydig cell tumor who also had a DICER1 mutation (Cowan M et al. Gynecol Oncol Rep, 2018 Aug;25:94-97). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 | Jul 11, 2022 | This missense variant replaces threonine with methionine at codon 993 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast cancer and one unaffected individual (PMID: 33471991, 33811135). This variant has been identified in 5/251460 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 specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
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 | May 23, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at