rs781663559
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024675.4(PALB2):āc.3122A>Cā(p.Lys1041Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_024675.4 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.3122A>C | p.Lys1041Thr | missense_variant | 11/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3122A>C | p.Lys1041Thr | missense_variant | 11/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135364
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1454620Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2AN XY: 724152
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2022 | The p.K1041T variant (also known as c.3122A>C), located in coding exon 11 of the PALB2 gene, results from an A to C substitution at nucleotide position 3122. The lysine at codon 1041 is replaced by threonine, an amino acid with similar properties. This alteration was reported in 1/360 Chinese women with hereditary breast cancer who previously tested negative for BRCA1 and BRCA2 mutations (Cao AY et al. Breast Cancer Res. Treat. 2009 Apr;114:457-62). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. 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 | Feb 15, 2022 | This missense variant replaces lysine with threonine at codon 1041 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 an individual affected with breast cancer (PMID: 18446436) and in a breast cancer case-control meta-analysis in 1/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010783). This variant has been identified in 1/250404 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 | GeneKor MSA | Aug 01, 2018 | - - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 14, 2023 | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1041 of the PALB2 protein (p.Lys1041Thr). This variant is present in population databases (rs781663559, gnomAD 0.0009%). This missense change has been observed in individual(s) with pediatric acute myeloid leukemia and a personal and/or family history of breast cancer (PMID: 18446436, 31159747, 31470354). ClinVar contains an entry for this variant (Variation ID: 422560). 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 not expected to disrupt PALB2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). 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 | Dec 20, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2016 | This variant is denoted PALB2 c.3122A>C at the cDNA level, p.Lys1041Thr (K1041T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant has been observed in at least one individual with either a personal or family history of breast and/or ovarian cancer (Cao 2009). PALB2 Lys1041Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. PALB2 Lys1041Thr occurs at a position that is not conserved and is located within the WD4 repeat region, a region required for interaction with POLH and POLH DNA synthesis stimulation, as well as a region of interaction with RAD51 and BRCA2 (UniProt). 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 Lys1041Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at