rs367840862
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The ENST00000261584.9(PALB2):c.3044C>T(p.Thr1015Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T1015N) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000261584.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3044C>T | p.Thr1015Ile | missense_variant | 10/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3044C>T | p.Thr1015Ile | missense_variant | 10/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 | |
ENST00000561764.1 | n.420-2469G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251446Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461826Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727220
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 19, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 06, 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1015 of the PALB2 protein (p.Thr1015Ile). This variant is present in population databases (rs367840862, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in PALB2 in at least one individual (Invitae), which suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 141554). 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%. 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 | May 18, 2023 | The p.T1015I variant (also known as c.3044C>T), located in coding exon 10 of the PALB2 gene, results from a C to T substitution at nucleotide position 3044. The threonine at codon 1015 is replaced by isoleucine, an amino acid with similar properties. In one study, this alteration was reported in 1/5488 control individuals and was not observed in 13087 breast cancer cases (Decker B et al. J Med Genet, 2017 11;54:732-741). 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 | Apr 27, 2020 | This missense variant replaces threonine with isoleucine at codon 1015 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 28779002). This variant has been identified in 3/251446 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2018 | Variant summary: The PALB2 c.3044C>T (p.Thr1015Ile) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/246228 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). This variant was found in at least one individual without clinical information (Decker_2017). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 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; This variant is associated with the following publications: (PMID: 33471991, 28779002, 19609323, 20871615, 24485656) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at